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November 2025
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Summary: Microplastics (MPs), particularly polyethylene microplastics (PE-MPs), are increasingly recognized as contaminants in both aquatic and terrestrial environments. However, the ecological impacts of PE-MPs on terrestrial organisms remain underexplored. This study investigates the physiological and behavioral effects of PE-MPs exposure in Drosophila melanogaster, shedding light on the potential risks posed by PE-MPs in land-based ecosystems. After exposing the fruit flies to different concentrations of PE-MPs for 20 days, several physiological biomarkers were assessed, including spontaneous behavioral activity, starvation resistance, metabolic biomarkers, and lifespan. The findings indicate that PE-MPs exposure significantly affects fruit fly physiology, with increased spontaneous activity, decreased starvation resistance, and reduced triglyceride (TG) and protein levels (in males), reflecting disruption of metabolic processes. While PE-MPs did not affect female reproductive capacity, they did result in sex-specific impacts on lifespan, with male fruit flies showing a significant reduction in both mean and median lifespan at higher PE-MPs concentrations. These results highlight the need to consider the sex-dependent nature of PE-MPs toxicity when assessing their ecological risks. This study contributes new insights into the potential for PE-MPs to disrupt terrestrial ecosystems and underscores the importance of investigating the effects of microplastics on terrestrial invertebrates, providing a foundation for future ecotoxicological research. | Rossano, A. J., Zhang, L., Anderson, J. B., Holmes, H. L., Mandal, A. K., Decker, J. W., Mount, D. B., Romero, M. F. (2025). Ex vivo quantification of intracellular pH in Drosophila Malpighian tubule reveals basolateral HCO(3) (-)/oxalate exchange through a novel oxalate transporter "Neat". Front Physiol, 16:1468451 PubMed ID: 40356774
Summary: Nephrolithiasis is a painful and costly healthcare complication. The most common kidney stones are composed of calcium oxalate and thus renal handling of oxalate is an important facet of understanding the pathogenesis of nephrolithiasis. Recently, the Drosophila melanogaster Malpighian tubule (MT) has emerged as a robust model of trans-epithelial ion transport and nephrolithiasis as MTs readily form luminal calcium-oxalate crystals in the presence of oxalate. Drosophila Prestin (dPrestin, Slc26a6) transports oxalate across the apical surface of the MT into the lumen. The objective of this work was to identify and characterize the Drosophila basolateral Ox(2-) transporter through ex vivo real-time quantification of intracellular pH (pH(i)). A putative basolateral oxalate transporter "CG5002 ("Neat") was identified through sequence homology and displayed robust Cl(-)-independent Ox(2-) transport and electroneutral Ox(2-) transport in Xenopus oocytes. pH(i) in extracted fly MTs was monitored. Basolateral perfusion of MTs in CO(2)/HCO(3) (-)-buffered solution produced a large acidification followed by rapid recovery in the transitional segment of the anterior MT. Recovery was interrupted by basolateral application of 1 mM Ox(2-) or 1 mM SO(4). Tissue specific knock-down of Neat with interference RNA (RNAi) reduced the rate of acid-loading in the transitional segment of the MT with regard to Ox(2-) and SO(4). Knockdown of Neat in the MT also significantly reduced luminal calcium oxalate crystal formation in a fly ex vivo model of calcium oxalate nephrolithiasis. These data indicate Neat is a significant Drosophila basolateral MT oxalate transporter and the basolateral movement of oxalate is functionally coupled to movement of acid equivalents, potentially as Ox(2-)/HCO(3) (-) exchange, Ox(2-)/OH(-) exchange, or Ox(2-):H(+) co-transport. |
| Rai, M., Li, H., Policastro, R. A., Pepin, R., Zentner, G. E., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). Glycolytic disruption restricts Drosophila melanogaster larval growth via the cytokine Upd3. PLoS Genet, 21(5):e1011690 PubMed ID: 40315265
Summary: Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate dehydrogenase (Ldh) and glycerol-3-phosphate dehydrogenase (Gpdh1) support this larval metabolic program by cooperatively promoting glycolytic flux. Consistent with their cooperative functions, the loss of both enzymes, but not either single enzyme alone, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the lethal phenotypes exhibited by Gpdh1; Ldh double mutants could be mediated non-autonomously. Supporting this possibility, the developmental arrest displayed by double mutants was found to extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, it was demonstrated that the simultaneous loss of Gpdh1 and Ldh results in elevated expression of Upd3, a cytokine involved in Jak/Stat signaling. Furthermore, upd3 loss-of-function mutations was shown to suppress the Gpdh1; Ldh larval arrest phenotype, indicating that Upd3 signaling restricts larval development in response to decreased glycolytic flux. Together, these findings reveal a mechanism by which metabolic disruptions can modulate systemic growth factor signaling. | Van De Poll, M. N., van Swinderen, B. (2025). Long-term multichannel recordings in Drosophila flies reveal altered predictive processing during sleep compared with wake. J Exp Biol, 228(11) PubMed ID: 40296777
Summary: During sleep, behavioral responsiveness to external stimuli is decreased. This classical definition of sleep has been applied effectively across the animal kingdom to identify this common behavioral state in a growing list of creatures, from mammals to invertebrates. Yet, it remains unclear whether decreased behavioral responsiveness during sleep is necessarily associated with decreased responsiveness in brain activity, especially in insects. Long-term multichannel electrophysiology was performed in tethered Drosophila melanogaster flies exposed continuously to repetitive visual stimuli. Flies were still able to sleep under these visual stimulation conditions, as determined by traditional immobility duration criteria for the field. Interestingly, this study did not find any difference between responses to repetitive visual stimuli during sleep compared with wake when we recorded local field potentials (LFPs) across a transect of the fly brain from optic lobes to the central brain. However, LFP responses were found to be altered when visual stimuli were variable and of lower probability, especially in the central brain. Central brain responses to less predictable or 'deviant' stimuli were lower during the deepest stage of sleep, a time of quiescence characterized by more regular proboscis extensions. This shows that the sleeping fly brain processes low-probability visual stimuli in a different way from more repeated stimuli, and presents Drosophila as a promising model for studying the potential role of sleep in regulating predictive processing. |
| Yu, G., Yang, Q., Wu, Q. (2025). Rapamycin Alters the Feeding Preference for Amino Acids and Sugar in Female Drosophila. J Gerontol A Biol Sci Med Sci, 80(7) PubMed ID: 40296844
Summary: Rapamycin has demonstrated significant lifespan-extending effects across a variety of model organisms, positioning it as one of the most promising antiaging agents currently under investigation. Nonetheless, chronic administration of rapamycin may induce diverse adverse reactions, primarily due to its influence on energy metabolism. Using Drosophila melanogaster as a model, this study showed that rapamycin significantly alters feeding behaviors in a dose-dependent manner. Specifically, both long-term and short-term administration of the optimal life-extending dose of rapamycin decreases the protein preference while increasing sugar intake in female flies. Utilizing a chemically defined diet, these alterations in amino acid and sugar feeding preferences were shown to occur as early as the second day of rapamycin exposure, preceding any detectable decline in fecundity. Furthermore, rapamycin also modifies amino acid preference even in taste-blind females, indicating that postingestive nutritional learning mechanisms, independent of food taste value, are sufficient to mediate the effects of rapamycin on feeding behavior. However, such changes in macronutrient preferences were absent in males and sterile mutant females. Collectively, this study suggests that the modification of feeding behavior could be a non-negligible side effect of rapamycin treatment, and this effect is influenced by both sex and reproductive status. | Subaric, D., Rastija, V., Karnas Babi , M., Agic, D., Majic, I. (2025). Structural Features of Coumarin-1,2,4-Triazole Hybrids Important for Insecticidal Effects Against Drosophila melanogaster and Orius laevigatus (Fieber). Molecules, 30(8) PubMed ID: 40333563
Summary: Although the present use of pesticides in plant protection has limited the occurrence and development of plant diseases and pests, resistance to pesticides and their environmental and health hazards indicates an urgent need for new active ingredients in plant protection products. Recently synthesized coumarin-1,2,4-triazole hybrid compounds have been proven effective against plant pathogenic fungi and safe for soil-beneficial bacteria. Drosophila melanogaster, the common fruit fly, has been used as a model organism for scientific research. Additionally, it is considered a pest since it damages fruits and serves as a carrier for various plant diseases. On the contrary, Orius laevigatus is a beneficial true bug that biologically controls harmful arthropods in agricultural production. In the present study, an adulticidal bioassay was performed against D. melanogaster and O. laevigatus using coumarin-1,2,4-triazole hybrids. Quantitative structure-activity relationship studies (QSARs) and in silico ecotoxicity evaluation elucidated the structural features underlying the compounds' insecticidal activity. The derivative of 4-methylcoumarin-1,2,4-triazole with a 3-bromophenyl group showed great insecticidal potential. A molecular docking study indicated that the most active compound probably binds to glutamate-gated chloride channels. |
Thursday, January 8th - Disease models |
| Ti, X., Zuo, H., Zhao, G., Li, Y., Du, M., Xu, L., Li, S., Shan, Z., Gao, Y., Gan, G., Wang, Y., Zhang, Q. (2025). Parkin mediates the mitochondrial dysfunction through mRpL18. J Biol Chem, 301(6):110208 PubMed ID: 40345588
Summary: Loss of function of parkin leads to mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One dogma is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, the first dogma is not applicable; for the second dogma, this study suggests that Parkin mediates mitochondrial dysfunction through the synergy of both Marf and mitochondrial protein mRpL18 got from a genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, this study found that impaired Parkin upregulated both transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing mRpL18 accumulation outside mitochondria. Consequently, cytosolic-accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways together drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, this study unveils a new facet of how Parkin regulates mitochondrial morphology, which provides new insights for the understanding and treatment of Parkinson's disease. | Scudese, E., Marshall, A. G., Vue, Z., Exil, V., ..., Sharma, V., Mobley, B. C., Katti, P., Hinton, A. (2025). 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes. Aging Cell:e70054 PubMed ID: 40285369
Summary: Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. This study sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers were correlate between young (under 50 years) and old (over 50 years) individuals. Mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which this study showed is required for the integrity of mitochondrial structure. Furthermore, this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. These results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2. |
| Tan, S. L., Neumann, D., Trim, P. J., Hewson, L. J., Mustaffar, N. F., He, Q. Q., Wimmer, N., Snel, M. F., Ferro, V., O'Keefe, L. V., Hemsley, K. M., Lau, A. A. (2025). Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome. Mol Genet Metab, 145(2):109112 PubMed ID: 40288156
Summary: Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). This study tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC Drosophila fed 4-deoxy-N-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders. | Singh, K., Gupta, K., Shukla, S., Kumari, A. P., Kumar, A. (2025). Repurposing Oseltamivir Against CAG Repeat Mediated Toxicity in Huntington's Disease and Spinocerebellar Ataxia Using Cellular and Drosophila Model. ACS Omega, 10(15):14980-14993 PubMed ID: 40290909
Summary: Huntington's disease (HD) and Spinocerebellar Ataxia (SCA) are debilitating neurological disorders triggered by the expansion of CAG sequences within the specific genes (HTT and ATXN, respectively). These are characterized as poly glutamine (polyQ) disorders, which are marked by widespread neurodegeneration and metabolic irregularities across systemic, cellular, and intracellular levels. This study aimed to identify small molecules that specifically interact with and target the toxic CAG repeat RNA. This study investigated the neuroprotective effects of Oseltamivir, an antiviral drug, against the HD and SCA-causing CAG repeats, through biophysical, cellular, and Drosophila model-based studies. Using a multidimensional approach encompassing biophysical techniques, cellular assays, and a Drosophila model, Oseltamivir's interaction with toxic CAG repeat RNA was explored. These comprehensive analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), and nuclear magnetic resonance (NMR) spectroscopy, demonstrated Oseltamivir's specific binding affinity for AA mismatches and its potential to mitigate the toxicity associated with polyQ aggregation. Moreover, the identified U.S. FDA-approved drug effectively mitigated polyQ-induced toxicity in both HD cells and the Drosophila model of the disease. The results obtained from this drug repurposing approach are indicative of the neuro-shielding role of Oseltamivir in HD and several SCAs, paving the way for its translation into clinical practice to benefit patients afflicted with these devastating diseases. |
| Song, H., Kim, S., Han, J. E., Kang, K. H., Koh, H. (2025). PDH Inhibition in Drosophila Ameliorates Sensory Dysfunction Induced by Vincristine Treatment in the Chemotherapy-Induced Peripheral Neuropathy Models. Biomedicines, 13(4) PubMed ID: 40299339
Summary: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting side effect of many effective anticancer agents, including vincristine. While CIPN adversely affects both oncological outcomes and the quality of life for cancer patients, the in vivo mechanisms behind CIPN pathology remain largely unknown, and effective treatments have yet to be developed. This study established a novel Drosophila model of CIPN using vincristine to explore the molecular mechanisms underlying this condition. The impact of vincristine exposure on thermal nociception in Drosophila larvae was assessed using a programmable heat probe. Additionally, vincristine-induced mitochondrial dysfunction and dendritic abnormalities in class IV dendritic arborization (C4da) neurons was investigated with various fluorescent protein markers. A dose-dependent increase in thermal hypersensitivity was found, accompanied by changes in the sensory dendrites of C4da neurons in vincristine-treated fly larvae. Moreover, vincristine significantly enhanced mitochondrial ROS production and mitophagy-a selective autophagy that targets dysfunctional mitochondria-indicating vincristine-induced mitochondrial dysfunction within C4da neurons. Surprisingly, inhibiting the pyruvate dehydrogenase complex (PDH), a key mitochondrial metabolic enzyme complex, effectively rescued the mitochondrial and sensory abnormalities caused by vincristine.Findings from this first Drosophila model of vincristine-induced peripheral neuropathy (VIPN) suggest that mitochondrial dysfunction plays a critical role in VIPN pathology, representing PDH as a potential target for the treatment of VIPN. | Serebryany-Piavsky, V., Egulsky, L., Manoim-Wolkovitz, J. E., Anis, S., Hassin-Baer, S., Parnas, M., Horowitz, M. (2025). The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease. Hum Mol Genet, 34(14):1184-1203 PubMed ID: 40315377
Summary: Parkinson disease (PD) is the second most common neurodegenerative disease. While most cases are sporadic, in ~5%-10% of PD patients the disease is caused by mutations in several genes, among them GBA1 (glucocerebrosidase beta 1) and LRRK2 (leucine-rich repeat kinase 2), both prevalent among the Ashkenazi Jewish population. LRRK2-associated PD tends to be milder than GBA1-associated PD. Several recent clinical studies have suggested that carriers of both GBA1 and LRRK2 mutations develop milder PD compared to that observed among GBA1 carriers. These findings strongly suggested an interplay between the two genes in the development and progression of PD. In the present study Drosophila was employed as a model to investigate the impact of mutations in the LRRK2 gene on mutant GBA1-associated PD. The results strongly indicated that flies expressing both mutant genes exhibited milder parkinsonian signs compared to the disease developed in flies expressing only a GBA1 mutation. This was corroborated by a decrease in the ER stress response, increase in the number of dopaminergic cells, elevated levels of tyrosine hydroxylase, reduced neuroinflammation, improved locomotion and extended survival. Furthermore, a significant decrease in the steady-state levels of mutant GBA1-encoded GCase was observed in the presence of mutant LRRK2, strongly implying a role for mutant LRRK2 in degradation of mutant GCase. |
Monday, January 5th - Larval and Adult Development |
| Lee, U., Li, C., Langer, C. B., Svetec, N., Zhao, L. (2025). Comparative single-cell analysis of transcriptional bursting reveals the role of genome organization in de novo transcript origination. Proc Natl Acad Sci U S A, 122(18):e2425618122 PubMed ID: 40305051
Summary: Spermatogenesis is a key developmental process underlying the origination of newly evolved genes. However, rapid cell type-specific transcriptomic divergence of the Drosophila germline has posed a significant technical barrier for comparative single-cell RNA-sequencing studies. By quantifying a surprisingly strong correlation between species- and cell type-specific divergence in three closely related Drosophila species, a statistical procedure was applied to identify a core set of 198 genes that are highly predictive of cell type identity while remaining robust to species-specific differences that span over 25 to 30 My of evolution. Then cell type classifications based on the 198-gene set were used to show how transcriptional. divergence in cell type increases throughout spermatogenic developmental time. After validating these cross-species cell type classifications using RNA fluorescence in situ hybridization and imaging, this study then investigated the influence of genome organization on the molecular evolution of spermatogenesis vis-a-vis transcriptional bursting. Altering transcriptional burst size was shown to contribute to premeiotic transcription and altering bursting frequency contributes to postmeiotic expression. Global differences in autosomal vs. X chromosomal transcription may arise in a developmental stage preceding full testis organogenesis were illustrated by showing evolutionarily conserved decreases in X-linked transcription bursting kinetics in all examined somatic and germline cell types. Finally, evidence is provided supporting the cultivator model of de novo gene origination by demonstrating how the appearance of newly evolved testis-specific transcripts potentially provides short-range regulation of neighboring genes' transcriptional bursting properties during key stages of spermatogenesis. | Wang, L., Bu, T., Gao, S., Yun, D., Chen, H., Cheng, C. Y., Sun, F. (2025). PCP protein Prickle 1 regulates Sertoli cell and testis function via cytoskeletal organization through the recruitment of multiple regulatory proteins. Am J Physiol Cell Physiol, 328(6):C2032-c2056 PubMed ID: 40327382
Summary: Prickle 1, an ortholog found in Drosophila, was localized at the Sertoli cell-spermatid interface consistent with its role of supporting the Vangl2 planar cell polarity (PCP), which is an integral membrane protein that creates the PCP protein complex of Vangl2 (Van Gogh-like 2)/Prickle1. Together with the asymmetrically localized transmembrane protein Frizzled (Fzd) and its unique adaptor proteins Disheveled (Dvl) and Inversin (Inv), Vangl2/Prickle1 and Fzd/Dvl/Inv are the two heterodimeric interacting PCP proteins between Sertoli cells and condensed spermatids to confer spermatid PCP across the plane of the seminiferous epithelium. The initial intention of this work was to examine if the distribution and expression of Prickle1 using a primary Sertoli cell in vitro model and Sprague-Dawley rats in vivo would mimic much of the earlier reported findings of Vangl2. Unexpectedly, these findings indicated that Prickle1 supported the PCP protein Vangl2; however, Prickle1 is also a multifunctional protein. First, Prickle1 knockdown (KD) by RNAi impeded Sertoli cell TJ function by perturbing the distribution of the BTB-associated proteins at the cell-cell interface, through disruption of the microtubule (MT) and actin cytoskeletal organization including their respective polymerization (and/or bundling) capability. Second, these findings were reproduced using an in vivo model of RNAi by KD of Prickle 1 in the testis. Third, using coimmunoprecipitation (Co-IP), Prickle 1 was found to interact with a host of adaptor proteins crucial to support not only PCP, such as Dvl, but also regulatory cytoskeletal proteins of MT and actin networks, including RhoA, Arp3, Cdc42, ZO-1, and β-catenin by immunoprecipitation-mass spectrometry (IP-MS) using the String Protein Interaction Tool. |
| Ku, H. Y., Bilder, D. (2025). Basement membrane patterning by spatial deployment of a secretion-regulating protease. Proc Natl Acad Sci U S A, 122(20):e2412161122 PubMed ID: 40359035
Summary: While paradigms for patterning of cell fates in development are well established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are not. Morphogenesis of the Drosophila egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose gradient creates tissue mechanical properties that specify the degree of elongation. This study shows that the gradient is not regulated by Col4 transcription but instead relies on posttranscriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypoelongation. Evidence is presented that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Meanwhile, the terminally expressed metalloprotease Stall increases Col4 turnover in the posterior. These data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape. | Simmons, C., Williams, I. H., Bradshaw, T. W., Armstrong, A. R. (2025). Adipocyte-Derived CCHamide-1, Eiger, Growth-Blocking Peptide 3, and Unpaired 2 Regulate Drosophila melanogaster Oogenesis. Biomolecules, 15(4) PubMed ID: 40305230
Summary: In addition to energy storage, adipose tissue communication to other organs plays a key role in regulating organismal physiology. While the link between adipose tissue dysfunction and pathophysiology, including diabetes, chronic inflammation, and infertility, is clear, the molecular mechanisms that underlie these associations have not been fully described. This study used Drosophila melanogaster as a model to better understand how adipose tissue communicates to the ovary. This study utilized D. melanogaster's robust genetic toolkit to examine the role of five adipokines known to control larval growth during development, CCHamide-1, CCHamide-2, eiger, Growth-blocking peptide 3, and unpaired 2 in regulating oogenesis. The adult fat body expresses these "larval" adipokines. The data indicate that ovarian germline stem cell maintenance does not require these adipokines. However, adipocyte-derived CCHamide-1, eiger, Growth-blocking peptide 3, and unpaired 2 influence early and late germline survival as well as ovulation. Thus, this work uncovers several adipokines that mediate fat-to-ovary communication. |
| Peng, J., Sun, A., Zheng, J., Zhang, N., Zhang, X., Gao, G. (2025). Testis-specific serine/threonine kinase dTSSK2 regulates sperm motility and male fertility in Drosophila. Commun Biol, 8(1):710 PubMed ID: 40335644
Summary: Serine/threonine kinases of the TSSK (Testis-Specific Serine/Threonine Kinase) family play crucial roles in spermatogenesis and male fertility across species, but the underlying regulatory mechanism remains incompletely understood. In this study, we identified and characterized a novel TSSK homolog in Drosophila, named dTSSK2 (CG9222), which functions as the ortholog of human TSSK4. dTSSK2 is specifically expressed in the testis and localizes to individualization complexes during spermiogenesis. Disruption of dTSSK2 severely compromises sperm motility, leading to failed sperm transit into the seminal vesicle and male infertility. Phosphoproteomic analyses reveal that dTSSK2 coordinates sperm flagella assembly and motility by phosphorylating proteins involved in microtubule organization, organelle assembly, and flagella structure. Notably, dTSSK2 phosphorylates the substrate Gudu at Ser9, which partially contributes to individualization complex integrity and sperm motility. These findings elucidate the critical role of dTSSK2-mediated phosphorylation in regulating Drosophila male fertility. | Otsune, S., Matsuka, M., Shirakashi, C., Zhang, X., Nakagoshi, H. (2025). Polished Rice Regulates Maturation but Not Survival of Secondary Cells in Drosophila Male Accessory Gland. Genes Cells, 30(3):e70025 PubMed ID: 40346918
Summary: In Drosophila males, the accessory gland is responsive to nutrient signal-dependent regulation of fertility/fecundity. The accessory gland is composed of two types of binucleated epithelial cells, about 1000 main cells and 60 secondary cells (SCs). The transcription factors Defective proventriculus (Dve), XF../segment/abdomlb1.htm">Abdominal-B, and Ecdysone receptors (EcRs) are strongly expressed in adult SCs. In response to nutrient conditions during development, coordinated action between Dve and ecdysone signaling determines the optimal number of SCs and regulates their maturation. A downstream effector of ecdysone signaling, Ftz-F1, is crucial in this process. Another downstream effector, Polished rice (Pri), is small peptides of 11 or 32 amino acids. This study shows that pri is required for maturation of SCs and for male fecundity, whereas it is not involved in determination of the number of SCs. Evidence is provided that Pri acts downstream of Ftz-F1 to regulate maturation but not survival of SCs. |
Monday,January 5th - Larval and Adult Development |
| Harsh, S., Liu, H. Y., Bhaskar, P. K., Rushlow, C., Bach, E. A. (2025). Post-transcriptional suppression of the pioneer factor Zelda protects the adult Drosophila testis from activation of the ovary program. PLoS Biol, 23(12):e3003535 PubMed ID: 41411219
Summary: Maintenance of somatic sex identity is essential for adult tissue function. In the Drosophila testis, adult somatic stem cells known as cyst stem cells (CySCs) require the transcription factor Chinmo to preserve male identity. Loss of Chinmo leads to reprogramming of CySCs into their ovarian counterparts through induction of the female-specific RNA-binding protein TransformerF (TraF), though the underlying mechanism has remained unclear. This study identified the pioneer transcription factor Zelda (Zld) as a critical mediator of this sex reversal. In wild-type CySCs, zld mRNA is repressed by microRNAs (miRs), but following Chinmo loss, these miRs are downregulated, allowing zld mRNA to be translated. Zld is necessary for feminization of chinmo-mutant CySCs, and ectopic expression of Zld in wild-type CySCs is sufficient to induce TraF and drive female reprogramming. Two Zld target genes, qkr58E-2 and Ecdysone receptor (EcR), are upregulated in chinmo-mutant CySCs and are normally female-biased in adult gonads. Qkr58E-2 facilitates TraF production, while EcR promotes female gene expression programs. Zld overexpression feminizes otherwise wild-type CySCs by upregulating EcR, which in turn downregulates the chinmo gene. Strikingly, overexpression of Zld also feminizes adult male adipose tissue by inducing TraF and downregulating Chinmo, indicating that Zld can override male identity in multiple adult XY tissues. Together, these findings uncover a post-transcriptional mechanism in which miRs-mediated repression of a pioneer factor safeguards male identity and prevents inappropriate activation of the female program in adult somatic cells. | Song, Y., Martin, P., Sun, T., Fernandez-Herrero, J., Sanchez-Herrero, E., Pastor-Pareja, J. C. (2025). Mechanical coupling between dorsal and ventral surfaces shapes the Drosophila haltere. Curr Biol, 35(13):3090-3105.e3095 PubMed ID: 40505664
Summary: The extracellular matrix is an essential determinant of animal form, enabling organization of cells and tissues into organs with complex shapes. In contrast with the dorso-ventrally flat Drosophila wing, its serial homolog, the haltere, adopts a globular shape thought to arise from a lack of matrix-mediated adhesion between its dorsal and ventral surfaces. Contradicting this model, however, matrix manipulations are known to deform halteres. To understand haltere morphogenesis, this study characterized matrix behavior and monitored metamorphic development of the haltere. Similar to the wing, correct haltere morphogenesis was found to require collagen IV degradation, which is mediated by ecdysone-controlled expression of matrix metalloprotease 2 in both wing and haltere. After collagen IV is degraded, similar again to the wing, dorsal and ventral haltere surfaces establish laminin-mediated contact through long cytoskeletal projections. Furthermore, time-lapse analysis of shape changes in wild-type and mutant halteres indicates that these projections couple the two surfaces through a central tensioner, ensuring load distribution across the whole organ to create a globular shape against tissue-wide deforming forces. These findings reveal an unexpected role for matrix-mediated adhesion in haltere morphogenesis and describe a novel type of matrix-based tensor structure building a 3D shape from 2D epithelia. |
| Bose, A., Schuster, K., Kodali, C., Sonam, S., Smith-Bolton, R. K. (2025). The pioneer transcription factor Zelda controls the exit from regeneration and restoration of patterning in Drosophila. Sci Adv, 11(23):eads5743 PubMed ID: 40479065
Summary: Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. This study found that in Drosophila wing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, targets of Zelda important for the end of regeneration were identified, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc. | Choi, B. J., Chen, Y. C., Desplan, C. (2025). Retinal Calcium Waves Coordinate Uniform Tissue Patterning of the Drosophila Eye. bioRxiv, PubMed ID: 40501815
Summary: Optimal neural processing relies on precise tissue patterning across diverse cell types. This study shows that spontaneous calcium waves arise among non-neuronal support cells in the developing Drosophila eye to drive retinal morphogenesis. Waves are initiated by Cad96Ca receptor tyrosine kinase signaling, triggering PLCγ-mediated calcium release from the endoplasmic reticulum. A cell-type-specific 'Innexin-code' coordinates wave propagation through a defined gap junction network among non-neuronal retinal cells, excluding photoreceptors. Wave intensity scales with ommatidial size, triggering stronger Myosin II-driven apical contractions at interommatidial boundaries in larger ommatidia. This size-dependent mechanism compensates for early boundary irregularities, ensuring uniform ommatidial packing critical for precise optical architecture. These findings reveal how synchronized calcium signaling among non-neuronal cells orchestrates tissue patterning in the developing nervous system. |
| Walker, B. M., Palumbo, R. J., Knutson, B. A. (2025). Tissue-specific requirement of Polr1D in the prothoracic gland for ecdysone-mediated developmental transitions in Drosophila melanogaster. Dev Dyn, PubMed ID: 40317818
Summary: Polr1D is a shared subunit of RNA Polymerases I and III, which transcribe the rRNA incorporated into ribosomes. Mutations in POLR1D cause Treacher Collins syndrome, a craniofacial disorder that arises from impaired ribosome biogenesis in neural crest cells. Previous work found that RNAi knockdown of Polr1D in several non-neural Drosophila tissues caused developmental defects that phenocopy mutations affecting ecdysone signaling. Ecdysone is a steroid hormone produced in the prothoracic gland (PG) of insects that triggers developmental transitions. This study shows that Polr1D is required for PG development and ecdysone production to facilitate larval developmental transitions. Polr1D RNAi in the PG causes larval developmental arrest due to defective peripheral ecdysone signaling. Polr1D is required for the growth of PG cells and for maintaining nucleolar structure. Polr1D was also shown to be required for the synthesis of mature ribosomes and the production of the Pol III-transcribed 7SK RNA. Furthermore, developmental arrest of Polr1D RNAi larvae and Polr1D mutant (G30R) larvae was partially rescued by treatment with exogenous ecdysone. These results demonstrate a role for Drosophila Polr1D in PG development and suggest that disruptions in human Polr1D might impact additional cell types during development. | Ready, D. F., Chang, H. C. (2025). Drosophila photoreceptor tethering by a laminin-Eys scaffold. iScience, 28(6):112732 PubMed ID: 40520108
Summary: Visual acuity in Drosophila requires precise photoreceptor alignment along the optical axis, maintained by longitudinal tension between a rigid cornea and a contractile retinal base. This study identified the rhabdomere caps-an extracellular matrix (ECM) structure that links rhabdomere tips to the integrin-decorated basal surfaces of overlying, lens-forming cone cells. Rhabdomere caps form perlecan-filled peaks shaped by a trapezoidal LanB1 (laminin) grid, which mirrors the inter-rhabdomeral space (IRS) contour. This study revealed that Eys (eyes shut), a photoreceptor-secreted proteoglycan essential for IRS formation, guides LanB1 and perlecan deposition by cone cells during pupal development. Disruption of LanB1 results in rhabdomere tip detachment, IRS collapse, and impaired tension transmission. These findings reveal that cone cells and photoreceptors collaboratively sculpt a rigid LanB1 grid that caps and reinforces the distal IRS lumen. This composite ECM structure preserves rhabdomere organization and evenly distributes mechanical forces, ensuring photoreceptor alignment and optical fidelity. |
Wednesday, December 31st - Disease Models |
| Sang, Y., Ning, X., Xu, Q., Wang, L., Yan, Y., Zhang, L., Bi, X. (2025). Characterization of transcriptomics during aging and genes required for lifespan in Drosophila intestine. Sci Rep, 15(1):14692 PubMed ID: 40287511
Summary: Aging is closely associated with imbalanced transcription. Regulated transcription in different organs is significantly different during aging, indicating that organ-specific transcriptomics is critical for understanding this process. This study analyzed the transcriptomics of the intestines of 3-, 15-, 30-, 40- and 50-days old female flies, which include young, middle-aged, and old flies. The differential expression of protein-coding genes and lncRNAs was found to be significant in aging, and fly age is characterized by well-separated gene expression trajectories. The highly clustered differentially expressed genes are connected to specific biological processes and signalling pathways. In particular, the Imd and Toll pathways are the top two immune signalling pathways that are highly regulated, and members with increased expression in the Imd pathway span all upstream activating events and include many ubiquitylation-associated factors and regulators of NF-κB factor Relish. Increased expression of Toll pathway members includes sensing mediators for all kinds of microorganisms and multiple proteases in the proteolytic processing cascade. Moreover, the expression of molecular markers of intestinal cells is greatly changed. Enterocyte markers are the most significantly influenced, and enteroendocrine markers AstA and NPF, as well as intestinal stem cell (ISC)/enteroblast (EB) markers Esg and Klu are expressed at low levels in young flies and much higher levels in aged flies. Furthermore, lncRNAs show similar expression trends and clustering patterns to those of protein-coding genes. Lastly, ISC/EB-specific knock-down of 13 out of 19 genes that are highly differentially expressed was found to reduce the lifespan of the fly. Together, the characterized transcriptomics and newly identified functional genes in aging will provide potential targets for preventing intestinal aging and associated disorders. | Hsiao, C. T., Fu, S. J., Cheng, K. M., Lo, H., Tang, C. Y., Chan, C. C., Jeng, C. J. (2025). Restoration of Shal/K(V)4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22. Cell Mol Life Sci, 82(1):181 PubMed ID: 40293501
Summary: Loss-of-function mutations in the human KCND3 gene encoding K(V)4.3 K(+) channels are linked to the autosomal dominant neurodegenerative disease spinocerebellar ataxia type 19/22 (SCA19/22). Previous biophysical and biochemical analyses in vitro support the notion that the autosomal dominant inheritance pattern of SCA19/22 is associated with the dominant-negative effects of disease-causing K(V)4.3 mutants on proteostasis of their wild-type (WT) counterpart. This study aimed to explore whether the disease-causing mutants might perturb protein expression of endogenous K(V)4.3 channel in human cells, as well as contributing to in vivo pathomechanisms underlying motor impairments and neurodegeneration in an animal model of SCA19/22. Substantial reduction in human K(V)4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human K(V)4.3, in Drosophila led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human K(V)4.3, but not K(V)1.1 K(+) channel. Transgenic expression of SCA19/22-causing human K(V)4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in Drosophila. Enhanced expression of the Drosophila molecular chaperones HSC70 and HSP83 in the fly model of SCA19/22 corrected Shal protein deficit, locomotor dysfunction, and neurodegeneration. Overexpression of Hsp90β also upregulated endogenous human K(V)4.3 protein level in patient-derived skin fibroblasts. These findings highlight Drosophila as a suitable animal model for studying K(V)4.3 channelopathy in vivo, and accentuate a critical role of defective K(V)4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22. Summary: |
| Kang, P., Liu, P., Hu, Y., Kim, J., Kumar, A., Dorneich-Hayes, M. K., Murzyn, W., Anderson, Z. J., Frank, L. N., Kavlock, N., Hoffman, E., Martin, C. C., Miao, T., Shimell, M., Powell-Coffman, J. A., O'Connor, M. B., Perrimon, N., Bai, H. (2025).. NF-kappaB-mediated developmental delay extends lifespan in Drosophila. Proc Natl Acad Sci U S A, 122(19):e2420811122. PubMed ID: 40339121
Summary: Developmental time (or time to maturity) strongly correlates with an animal's maximum lifespan, with late-maturing individuals often living longer. However, the genetic mechanisms underlying this phenomenon remain largely unknown. This may be because most previously identified longevity genes regulate growth rate rather than developmental time. To address this gap, this study genetically manipulated prothoracicotropic hormone (PTTH), the primary regulator of developmental timing in Drosophila, to explore the genetic link between developmental time and longevity. Loss of PTTH delays developmental timing without altering the growth rate. Intriguingly, PTTH mutants exhibit extended lifespan despite their larger body size. This lifespan extension depends on ecdysone signaling, as feeding 20-hydroxyecdysone to PTTH mutants reverses the effect. Mechanistically, loss of PTTH blunts age-dependent chronic inflammation, specifically in fly hepatocytes (oenocytes). Developmental transcriptomics reveal that NF-κB signaling activates during larva-to-adult transition, with PTTH inducing this signaling via ecdysone. Notably, time-restricted and oenocyte-specific silencing of Relish (an NF-κB homolog) at early 3rd instar larval stages significantly prolongs adult lifespan while delaying pupariation. Our study establishes an aging model that uncouples developmental time from growth rate, highlighting NF-κB signaling as a key developmental program in linking developmental time to adult lifespan. | Hafeez, E., Du, D., Ni, H., Zhu, K., Hu, F., Zhou, J., Chen, D. (2025). Regulation and mechanism of Bletilla striata polysaccharide on delaying aging in Drosophila melanogaster. Int J Biol Macromol, 310(Pt 3):143382 PubMed ID: 40268010
Summary: Bletilla striata polysaccharide (BSP) is a natural bioactive compound known for its promising health benefits, including antioxidant, immunomodulatory, and anti-inflammatory effects. However, its potential in combating aging remains largely unexplored. This study aims to investigate the anti-aging effects of BSP in the Drosophila melanogaster model. The results show that BSP supplementation significantly extends the lifespan of flies in a concentration-dependent manner, with the most pronounced effects observed at a concentration of 3 mg/mL. Lifespan extension is associated with enhanced antioxidative capacities, as evidenced by increased SOD and CAT activities, and decreased MDA (malondialdehyde, a key chemical biomarker used to measure oxidative stress and lipid damage in biological and food systems) content. Additionally, BSP ameliorates age-related symptoms, including improved climbing ability and enhanced intestinal barrier function. Furthermore, BSP supplementation enhances resistance to H(2)O(2)-induced oxidative and starvation stresses, attenuates the lead (Pb)-induced toxicity, and delays the onset of Alzheimer's phenotypes in flies. RNA-Seq analysis reveals that BSP supplementation leads to the differential expression of 992 genes. KEGG pathway analysis highlights significant changes in metabolic pathways, including galactose metabolism, starch and sucrose metabolism, and carbon metabolism. Key genes such as Mal-A1, Amy-d, Men-b, Pgm-1, Mdh1, and Hex-C are downregulated, while CG32026, CG11291, and Ald2 are upregulated. These findings suggest BSP exhibits significant anti-aging and protective properties, making it a potential therapeutic agent. |
| Malik, T., Sidisky, J. M., Jones, S., Winters, A., Hocking, B., Rotay, J., Huhulea, E. N., Moran, S., Connors, B., Babcock, D. T. (2025). Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis. Hum Mol Genet, 34(14):1204-1215 PubMed ID: 40327885
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, defects in synaptic integrity are among the earliest hallmarks of ALS. However, the specific impairments to synaptic integrity remain unclear. To better understand synaptic defects in ALS, this study expressed either wild-type or mutant Fused in Sarcoma (FUS), an RNA binding protein that is often mis-localized in ALS, in adult motor neurons. Using optogenetic stimulation of the motor neurons innervating the Ventral Abdominal Muscles (VAMs), expression of mutant FUS was found to disrupt the functional integrity of these synapses. This functional deficit was followed by disruption of synaptic gross morphology, localization of pre- and post-synaptic proteins, and cytoskeleton integrity. Similar synaptic defects were found using the motor neurons innervating the Dorsal Longitudinal Muscles (DLMs), where expression of mutant FUS resulted in a progressive loss of flight ability along with disruption of active zone distribution. These findings uncover defects in synaptic function that precede changes in synaptic structure, suggesting that synaptic function is more sensitive to this ALS model. Highlighting the earliest synaptic defects in this disease model should help to identify strategies for preventing later stages of disease progression. | Sasaki, S., Satoh, R., Satoh, T., Satoh, A. K. (2025). Lytic photoreceptor cell death caused by Rab escort protein deficiency in Drosophila. FEBS Lett, PubMed ID: 40325959
Summary: Choroideremia (CHM) is a rare X-lisnked recessive form of inherited retinal degeneration caused by the deficiency of the Rab escort protein 1 (REP1)-encoding CHM gene. REP1 is essential for the post-translational prenylation of the key players in intracellular membrane trafficking, the Rab GTPases. This study aimed to analyze the mechanisms of retinal degeneration caused by Rep deficiency using the Drosophila retina as a model system. Rab GTPases lost their membrane association ability and diffused into the cytoplasm, and the accumulation of unprenylated Rab6 and Rab7 was observed in Rep-deficient photoreceptors. Notably, Rep-deficient photoreceptors underwent progressive cell death via cell swelling and rupture rather than apoptosis. These findings provide new insight to seek a therapeutic approach to CHM. |
Monday, December 29th - Larval and Adult Neural Structure, Development and Functio |
| Sarnataro, R., Velasco, C. D., Monaco, N., Kempf, A., Miesenbock, G. (2025). Mitochondrial origins of the pressure to sleep. Nature, 645(8081):722-728 PubMed ID: 40670797
Summary: To gain a comprehensive, unbiased perspective on molecular changes in the brain that may underlie the need for sleep, this study has characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies. Transcripts upregulated after sleep deprivation, in sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) but not ubiquitously in the brain, encode almost exclusively proteins with roles in mitochondrial respiration and ATP synthesis. These gene expression changes are accompanied by mitochondrial fragmentation, enhanced mitophagy and an increase in the number of contacts between mitochondria and the endoplasmic reticulum, creating conduits for the replenishment of peroxidized lipids. The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow in the respiratory chain. Inducing or preventing mitochondrial fission or fusion in dFBNs alters sleep and the electrical properties of sleep-control cells in opposite directions: hyperfused mitochondria increase, whereas fragmented mitochondria decrease, neuronal excitability and sleep. ATP concentrations in dFBNs rise after enforced waking because of diminished ATP consumption during the arousal-mediated inhibition of these neurons, which augments their mitochondrial electron leak. Consistent with this view, uncoupling electron flux from ATP synthesis relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump) precipitates sleep. Sleep, like ageing, may be an inescapable consequence of aerobic metabolism. | Sturner, T., Brooks, P., Serratosa Capdevila, L., Morris, B., ...., Tuthill, J. C., Lee, W. A., Card, G. M., Costa, M., Jefferis, G., Eichler, K. (2025). Comparative connectomics of Drosophila descending and ascending neurons. Nature, 643(8070):158-172 PubMed ID: 40307549
Summary: In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and an information bottleneck connecting the brain and the ventral nerve cord (an analogue of the spinal cord) and comprises diverse populations of descending neurons (DNs), ascending neurons (ANs) and sensory ascending neurons, which are crucial for sensorimotor signalling and control. By integrating three separate electron microscopy (EM) datasets, this study provides a complete connectomic description of the ANs and DNs of the Drosophila female nervous system and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions are matched across hemispheres, datasets and sexes. Crucially, 51% of DN cell types were also matched to light-level data defining specific driver lines, as well as classifying all ascending populations. These results were used to reveal the anatomical and circuit logic of neck connective neurons. Connected chains of DNs and ANs were observed spanning the neck that may subserve motor sequences. A complete description is provided of sexually dimorphic DN and AN populations, with detailed analyses of selected circuits for reproductive behaviours, including male courtship (DNa12; also known as aSP22) and song production (AN neurons from hemilineage 08B) and female ovipositor extrusion (DNp13). This work provides EM-level circuit analyses that span the entire central nervous system of an adult animal. |
| Li, J., Dhaliwal, R., Stanley, M., Junca, P., Gordon, M. D. (2025). Functional imaging and connectome analyses reveal organizing principles of taste circuits in Drosophila. Curr Biol, 35(10):2391-2405.e2394 PubMed ID: 40334663
Summary: Taste is crucial for many innate and learned behaviors. In the fruit fly, Drosophila melanogaster, taste impacts processes including feeding, oviposition, locomotion, mating, and memory formation. These diverse roles may necessitate the apparent distributed nature of taste responses across different circuits in the fly brain, leading to complexity that has hindered attempts to deduce unifying principles of taste processing and coding. This study combined information from the whole-brain connectome with functional calcium imaging to examine the neural representation of taste at early steps of processing. The majority of taste-responsive cells in the subesophageal zone (SEZ), including local interneurons (SEZ-LNs) and projection neurons (SEZ-PNs) targeting the superior protocerebrum, are predicted to encode a single taste modality. This prediction is borne out by calcium imaging of cholinergic and GABAergic cells in the SEZ, as well as five representative SEZ-PNs. Although the connectome reveals some SEZ-PNs receiving direct inputs from sensory neurons, many receive primarily indirect taste inputs via cholinergic SEZ-LNs. These cholinergic SEZ-LNs appear to function as nodes to convey feedforward information to dedicated sets of morphologically similar SEZ-PNs. Together, these studies suggest a previously unappreciated logic and structure to fly taste circuits. | Iyer, A. R., Scholz-Carlson, E., Bell, E., Biondi, G., Richhariya, S., Fernandez, M. P. (2025). Circadian rhythms are more resilient to pacemaker neuron disruption in female Drosophila. PLoS Biol, 23(5):e3003146 PubMed ID: 40327674
Summary: The circadian system regulates the timing of multiple molecular, physiological, metabolic, and behavioral phenomena. In Drosophila, as in other species, most of the research on how the timekeeping system in the brain controls the timing of behavioral outputs has been conducted in males, or sex has not been included as a biological variable. A critical set of circadian pacemaker neurons in Drosophila release the neuropeptide pigment-dispersing factor (PDF), which functions as a key output factor in the network with complex effects on other clock neurons. Lack of Pdf or its receptor, PdfR, results in most flies displaying arrhythmicity in activity-rest cycles under constant conditions. However, the current results show that female circadian rhythms are less affected by mutations in both Pdf and PdfR. CRISPR-Cas9-mediated mutagenesis of Pdf, specifically in ventral lateral neurons (LNvs), also has a greater effect on male rhythms. The influence of M-cells on the circadian network was tested, and speeding up the molecular clock specifically in M-cells led to sexually dimorphic phenotypes, with a more pronounced effect on male rhythmic behavior. These results suggest that the female circadian system is more resilient to manipulations of M-cells and the PDF pathway, suggesting that circadian timekeeping is more distributed across the clock neuron network in females. |
| Lyu, C., Li, Z., Xu, C., Wong, K. K. L., Luginbuhl, D. J., McLaughlin, C. N., Xie, Q., Li, T., Li, H., Luo, L. (2025). Dimensionality reduction simplifies synaptic partner matching in an olfactory circuit. Science, 388(6746):538-544 PubMed ID: 40310920
Summary: A navigating axon faces complex choices when selecting postsynaptic partners in a three-dimensional (3D) space. In this work a principle was discovered that can establish the 3D glomerular map of the fly antennal lobe by reducing the higher dimensionality serially to 1D projections. During development, olfactory receptor neuron (ORN) axons first contact their partner projection neuron dendrites on the spherical surface of the antennal lobe, regardless of whether the adult glomeruli lie near the surface or inside. Along this 2D surface, axons of each ORN type take a specific, arc-shaped trajectory that precisely intersects with their partner dendrites. Altering axon trajectories compromises synaptic partner matching. A 3D search is thus reduced to one dimension, simplifying partner matching. | Saltin, B. D., Goldsmith, C., Haustein, M., Buschges, A., Szczecinski, N. S., Blanke, A. (2025). A parametric finite element model of leg campaniform sensilla in Drosophila to study campaniform sensilla location and arrangement. J R Soc Interface, 22(226):20240559 PubMed ID: 40329924
Summary: Campaniform sensilla (CS) are mechanosensors embedded in the cuticle of insects. They are often found at locations near the joints of leg segments. On legs, CS are generally considered to respond directionally to cuticle bending during legged locomotion. It is currently unclear how CS locations affect strain levels at the CS, but this information is crucial for understanding how CS respond to stimuli. This study presents a parametric finite element model of the femoral CS field for Drosophila hind legs with 12 general and seven CS-specific parameters each. This model allows testing how changes in CS location, orientation and material property affect strain levels at each CS. Experimentally acquired kinematic data was used, and ground reaction forces were computed to simulate in vivo-like forward stepping. The displacements found in this study at the physiological CS field location near the trochanter-femur joint are smaller than those necessary for conformation changes of ion channels involved in signal elicitation. Also, variation of material properties of the CS had little influence on displacement magnitudes at the CS cap where the sensory neuron attaches. Thus, these results indicate that ground reaction forces alone are unlikely to serve CS field activation during forward walking. |
Friday, December 26th - Transposons and RNAi |
| Rousseau, C., Morand, T., Haas, G., Lauret, E., Kuhn, L., Chicher, J., Hammann, P., Meignin, C. (2025). In vivo Dicer-2 interactome during viral infection reveals novel pro and antiviral factors in Drosophila melanogaster. PLoS Pathog, 21(5):e1013093 PubMed ID: 40334246
Summary: RNA interference has a major role in the control of viral infection in insects. It is initialized by the sensing of double stranded RNA (dsRNA) by the RNAse III enzyme Dicer-2. Many in vitro studies have helped understand how Dicer-2 discriminates between different dsRNA substrate termini, however it is unclear whether the same mechanisms are at work in vivo, and notably during recognition of viral dsRNA. Indeed, although Dicer-2 associates with several dsRNA-binding proteins (dsRBPs) that can modify its specificity for a substrate, it remains unknown how Dicer-2 is able to recognize the protected termini of viral dsRNAs. In order to study how the ribonucleoprotein network of Dicer-2 impacts antiviral immunity, an IP-MS approach was used to identify in vivo interactants of different versions of GFP::Dicer-2 in transgenic lines. A global overview is provided of the partners of Dicer-2 in vivo, and reveal how this interactome is modulated by different factors such as viral infection and/or different point mutations inactivating the helicase or RNase III domains of GFP::Dicer-2. The analysis uncovers several previously unknown Dicer-2 interactants associated with RNA granules, i.e., Me31B, Rump, eIF4E1, eIF4G1, Rin and Syncrip. Functional characterization of the candidates, both in cells and in vivo, reveals pro- and antiviral factors in the context of an infection by the picorna-like DCV virus. This work highlights protein complexes assembled around Dicer-2 in vivo, and provides a resource to investigate their contribution to antiviral RNAi and related pathways. | Akulenko, N., Mikhaleva, E., Marfina, S., Kutelev, I., Kornyakov, D., Bobrov, V., Artamonov, A., Arapidi, G., Shender, V., Ryazansky, S. (2025). Insights into the target-directed miRNA degradation mechanism in Drosophila ovarian cell culture. Biochim Biophys Acta Gene Regul Mech, 1868(2):195092 PubMed ID: 40328417
Summary: Target-directed miRNA degradation (TDMD) is a process of post-transcriptional regulation of miRNA stability in animals induced by an extended pairing of Ago-bound miRNAs with specialized complementary RNA targets. As suggested by studies on human cell culture, Ago engaged with the extended duplex is recognized by the ZSWIM8 receptor of the Cullin-RING-ligase complex (CRL3), which also contains Cul3, EloB, and EloC proteins. The CRL activity is accelerated by the neddylation of Cul3 with the involvement of the E2 conjugating protein UbcE2M. The CRL ubiquitinates Ago, resulting in proteolysis of Ago and degradation of the released miRNAs. To date, the molecular mechanism of TDMD has not been studied in other species. To further characterize TDMD in animals, this study investigated the protein Dora, the Drosophila ortholog of ZSWIM8, in the culture of Drosophila ovarian somatic cells (OSC). Dora in OSCs is shown to localize in protein granules unrelated to P- and GW-bodies. The dora knockout resulted in the accumulation of multiple miRNAs, including miR-7-5p, and transcriptome-wide affected the mRNA targets of differentially expressed miRNAs. Dora associates with proteins of the CRL3 complex, and the depletion of CRL3 components or inhibition of Cul3 neddylation upregulates miR-7-5p. It is concluded that the molecular mechanism of TDMD is conserved in humans and Drosophila. Finally, cells without Dora were found to have an impaired Notch signaling pathway, indicating that TDMD in OSCs may contribute to the modulation of the Notch pathway. |
| Tracy, L., Zhang, Z. Z. (2025). Safeguarding spermatogenesis from retrotransposon insertions by forming ecDNA. bioRxiv, PubMed ID: 40462890
Summary: Retrotransposon mobilization in germline cells enables the rewriting of genetic information to drive genome innovation, species evolution, and adaptation through the generation of de novo mutations. However, uncontrolled mobilization can cause DNA breaks and genome instability, often leading to sterility. How germ cells balance retrotransposon-induced genome innovation with the need for genomic integrity remains poorly understood. This study used Drosophila spermatogenesis as a model to investigate retrotransposon mobilization dynamics. Although many retrotransposon families are transcriptionally active, the LTR-retrotransposon nomad (for information on nomad, go to Google AI and query 'Retrotransposon nomad Drosophila') was found to complete the full mobilization cascade-including mRNA export, protein translation, and reverse transcription-to produce double-stranded DNA (dsDNA) the most efficiently. Strikingly, despite successfully generating dsDNA, nomad rarely achieves genomic reintegration. Instead, its newly synthesized DNA predominantly forms extrachromosomal circular DNA (ecDNA). These findings suggest that ecDNA formation acts as a protective mechanism to sequester retrotransposon-derived DNA and prevent widespread genomic integration during spermatogenesis, thereby preserving genome stability while allowing limited retrotransposon activity. | Hwang, H. J., Sheard, K. M., Cox, R. T. (2025). Drosophila Clu ribonucleoprotein particle dynamics rely on the availability of functional Clu and translating ribosomes. J Cell Sci, 138(9) PubMed ID: 40302698
Summary: Drosophila Clu is a conserved multi-domain ribonucleoprotein essential for mitochondrial function that forms dynamic particles within the cytoplasm. Unlike stress granules and processing bodies (P-bodies), Clu particles disassemble under nutritional or oxidative stress. However, it is unclear how disrupting protein synthesis affects Clu particle dynamics, especially given that Clu binds mRNA and ribosomes. This study capitalized on ex vivo and in vivo imaging of Drosophila female germ cells to determine what domains of Clu are necessary for Clu particle assembly and how manipulating translation affects particle dynamics. Using domain deletion analysis, three domains of Clu essential for particle assembly were identified. Overexpressing functional Clu led to disassembly of particles. In addition, translation was inhibited using cycloheximide and puromycin. In contrast to P-bodies, cycloheximide treatment did not disassemble Clu particles yet puromycin treatment did. Surprisingly, cycloheximide stabilized particles under oxidative and nutritional stress. These findings demonstrate that Clu particles display novel dynamics in response to altered ribosome activity and support a model where they function as translation hubs whose assembly heavily depends on the dynamic availability of translating ribosomes. |
| Narbonne-Reveau, K., Erni, A., Eichner, N., Sankar, S., Kapoor, S., Meister, G., Cremer, H., Maurange, C., Beclin, C. (2025). In vivo AGO-APP identifies a module of microRNAs cooperatively preserving neural progenitors. PLoS Genet, 21(4):e1011680 PubMed ID: 40299997
Summary: MicroRNAs are essential regulators of gene expression. Their function is particularly important during neurogenesis, when the production of large numbers of neurons from a limited number of neural stem cells depends on the precise control of determination, proliferation and differentiation. However, microRNAs can target many mRNAs and vice-versa, raising the question of how specificity is achieved to elicit a precise regulatory response. This study introduces in vivo AGO-APP, a novel approach to purify Argonaute-bound, and therefore active microRNAs from specific cell types. Using AGO-APP in the larval Drosophila central nervous system,a module of microRNAs predicted to redundantly target all iconic genes known to control the transition from neuroblasts to neurons. While microRNA overexpression generally validated predictions, knockdown of individual microRNAs did not induce detectable phenotypes. In contrast, neuroblasts were induced to differentiate precociously when several microRNAs were knocked down simultaneously. These data supports the concept that at physiological expression levels, the cooperative action of miRNAs allows efficient targeting of entire gene networks. | Hayashi, M., Koga, Y., Kozono, Y., Kobayashi, S. (2025). Maternal ovo represses the expression of transposable elements in adult ovaries. Dev Biol, 523:111-114 PubMed ID: 40280385
Summary: In germ cells, repressing transposable elements (TEs) is important to maintain genomic integrity. TE expression and transposition are repressed by PIWI-interacting RNAs (piRNAs). Although many genes for piRNA synthesis have been described, few transcription factors activating their expression have been identified. It has been previously reported that a transcription factor, maternal Ovo (Ovo-B) protein activates germline-specific gene expression in progenitors of germ cells. This study found that maternal Ovo also activates several genes, including aubergine (aub), for TE silencing. Knocking down maternal Ovo de-repressed TEs in adult ovaries. In addition, embryonic knockdown of aub caused de-repression of TEs in adult Drosophila ovaries. Surprisingly, embryonic knockdown of maternal Ovo affected neither expression of ovo nor its downstream TE-silencing genes in adult ovaries after growth. These results strongly suggest that maternal Ovo is required for TE silencing in ovaries, via transcriptional activation of genes for piRNA synthesis in embryos. |
Monday, December 22nd - Evolution |
| Luo, Y., Takau, A., Li, J., Fan, T., Hopkins, B. R., Le, Y., Ramirez, S. R., Matsuo, T., Kopp, A. (2025). Regulatory changes in the fatty acid elongase eloF underlie the evolution of sex-specific pheromone profiles in Drosophila prolongata. BMC Biol, 23(1):117 PubMed ID: 40307835
Summary: Pheromones play a key role in regulating sexual behavior throughout the animal kingdom. In Drosophila and other insects, many cuticular hydrocarbons (CHCs) are sexually dimorphic, and some are known to perform pheromonal functions. However, the genetic control of sex-specific CHC production is poorly understood outside of the model species D. melanogaster. A recent evolutionary change is found in D. prolongata, which, compared to its closest relatives, shows greatly increased sexual dimorphism in both CHCs and the chemosensory system responsible for their perception. A key transition involves a male-specific increase in the proportion of long-chain CHCs. Perfuming D. prolongata females with the male-biased long-chain CHCs reduces copulation success, suggesting that these compounds function as sex pheromones. The evolutionary change in CHC profiles correlates with a male-specific increase in the expression of multiple genes involved in CHC biosynthesis, including fatty acid elongases, reductases and other key enzymes. In particular, elongase F, which is responsible for producing female-specific pheromones in D. melanogaster, is strongly upregulated in D. prolongata males compared both to females and to males of the sibling species. Mutations in eloF reduce the amount of long-chain CHCs, resulting in a partial feminization of pheromone profiles in D. prolongata males. Transgenic experiments show that sex-biased expression of eloF is caused in part by a putative transposable element honghaier insertion in its regulatory region. These results show that cis-regulatory changes in the eloF gene, along with other changes in the CHC synthesis pathway, contribute to the evolution of sexual communication. | Rethemeier, S., Fritzsche, S., Muhlen, D., Bucher, G., Hunnekuhl, V. S. (2025). Differences in size and number of embryonic type II neuroblast lineages correlate with divergent timing of central complex development between beetle and fly. Elife, 13 PubMed ID: 40326533
Summary: The insect brain and the timing of its development underwent evolutionary adaptations. However, little is known about the underlying developmental processes. The central complex of the brain is an excellent model to understand neural development and divergence. It is produced in large parts by type II neuroblasts, which produce intermediate progenitors, another type of cycling precursor, to increase their neural progeny. Type II neuroblasts lineages are believed to be conserved among insects, but little is known on their molecular characteristics in insects other than flies. Tribolium castaneum has emerged as a model for brain development and evolution. However, type II neuroblasts have so far not been studied in this beetle. A fluorescent enhancer trap was created marking expression of Tc-fez/earmuff, a key marker for intermediate progenitors. Using combinatorial labeling of further markers, including Tc-pointed, embryonic type II neuroblast lineages were characterized. Intriguingly, nine lineages per hemisphere were found in the Tribolium embryo while Drosophila produces only eight per brain hemisphere. These embryonic lineages are significantly larger in Tribolium than they are in Drosophila and contain more intermediate progenitors. Finally, these lineages were mapped to the domains of head patterning genes. Notably, Tc-otd is absent from all type II neuroblasts and intermediate progenitors, whereas Tc-six3 marks an anterior subset of the type II lineages. Tc-six4 specifically marks the territory where anterior-medial type II neuroblasts differentiate. The higher number and greater lineage size of the embryonic type II neuroblasts in the beetle correlate with a previously described embryonic phase of central complex formation. These findings stipulate further research on the link between stem cell activity and temporal and structural differences in central complex development. |
| Riedelbauch, S., Masser, S., Fasching, S., Lin, S. Y., Salgania, H. K., Aarup, M., Ebert, A., Jeske, M., Levine, M. T., Stelzl, U., Andersen, P. (2025). Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway. Embo j, PubMed ID: 40275032
Summary: Despite being essential for fertility, genome-defense-pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. This study characterized the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome-defense pathway in Drosophila at unprecedented scale and evolutionary resolution. The pervasive rapid evolution of a protein interaction network was uncovered, anchored at the heterochromatin protein 1 (HP1) paralog Rhino. Through cross-species high-throughput yeast-two-hybrid screening, three distinct evolutionary protein interaction trajectories were identified across ~40 million years of Drosophila evolution. While several protein interactions are fully conserved, indicating functional conservation despite rapid amino acid-sequence change, other interactions are preserved through coevolution and were detected only between proteins within or from closely related species. Species-restricted protein interactions were identified, revealing insight into the mechanistic diversity and ongoing molecular innovation in Drosophila piRNA production. In sum, this analyses reveal principles of interaction evolution in an adaptively evolving protein-protein interaction network, and support intermolecular interaction innovation as a central molecular mechanism of evolutionary adaptation in protein-coding genes. | Lee, D., Shahandeh, M. P., Abuin, L., Benton, R. (2025). Comparative single-cell transcriptomic atlases of drosophilid brains suggest glial evolution during ecological adaptation. PLoS Biol, 23(4):e3003120 PubMed ID: 40299832
Summary: To explore how brains change upon species evolution, single-cell transcriptomic atlases were generated of the central brains of three closely related but ecologically distinct drosophilids: the generalists Drosophila melanogaster and Drosophila simulans, and the noni fruit specialist Drosophila sechellia. The global cellular composition of these species' brains is well-conserved, but a few cell types were predicted with different frequencies, notably perineurial glia of the blood-brain barrier, which was validated in vivo. Gene expression analysis revealed that distinct cell types evolve at different rates and patterns, with glial populations exhibiting the greatest divergence between species. Compared to the D. melanogaster brain, cellular composition and gene expression patterns are more divergent in D. sechellia than in D. simulans-despite their similar phylogenetic distance from D. melanogaster-indicating that the specialization of D. sechellia is reflected in the structure and function of its brain. Expression changes in D. sechellia include several metabolic signaling genes, suggestive of adaptations to its novel source of nutrition. Additional single-cell transcriptomic analysis on D. sechellia revealed genes and cell types responsive to dietary supplement with noni, pointing to glia as sites for both physiological and genetic adaptation to this fruit. These atlases represent the first comparative datasets for "whole" central brains and provide a comprehensive foundation for studying the evolvability of nervous systems in a well-defined phylogenetic and ecological framework. |
| Keais, G. L., Saad-Roy, C. M., Gonzalez-Sqalli, E., Powell, C. N., Rieseberg, L. H., Gawryluk, R. M. R., van den Driessche, P., Wei, K. H., Loppin, B., Perlman, S. J. (2025). A selfish supergene causes meiotic drive through both sexes in Drosophila. Proc Natl Acad Sci U S A, 122(17):e2421185122 PubMed ID: 40267129
Summary: Meiotic drivers are selfish genetic elements that bias their own transmission during meiosis or gamete formation. Due to the fundamental differences between male and female meiosis in animals and plants, meiotic drivers operate through distinct mechanisms in the two sexes: In females, they exploit the asymmetry of meiosis to ensure their inclusion in the egg, whereas in males, they eliminate competing gametes after symmetric meiosis. Meiotic drive is commonly reported in males, where it strongly influences the evolution of spermatogenesis, while the few known cases in females have highlighted its crucial role in centromere evolution. Despite a growing number of examples in a wide range of organisms, meiotic drive has so far only been observed in one sex or the other since its discovery nearly 100 y ago. This study shows that a selfish X chromosome known to cause meiotic drive in male Drosophila testacea flies also causes meiotic drive in females. This X chromosome has supergene architecture, harboring extensive structural rearrangements that suppress recombination between the two X chromosomes. This has contributed to a substantial expansion of its size compared to the wild-type chromosome, partly due to the accumulation of species-specific repetitive elements. These findings suggest that female meiotic drive may play an important role in the evolutionary dynamics of polymorphic structural variants that suppress recombination, including inversions, translocations, and supergenes. | Kao, J. A., Ewen-Campen, B., Extavour, C. G. (2025). Divergence of germ cell-less roles in germ line development across insect species. Dev Biol, 525:93-101 PubMed ID: 40334835
Summary: During development, sexually reproducing animals must specify and maintain the germ line, the lineage of cells that gives rise to the next generation of animals. In the fruit fly Drosophila melanogaster, germ cell-less (gcl) is required for the formation of primordial germ cells in the form of cells that cellularize at the posterior pole of the embryo, called pole cells. Forming pole cells is a mechanism of germ cell formation unique to a subset of insects. Even though most animals do not form pole cells as primordial germ cells, gcl is conserved across Metazoa, raising the question of how this conserved gene acquired its central role in the evolutionarily derived process of pole cell formation. This study examined the functions of gcl in two other insects with different modes of germ cell specification: the milkweed bug Oncopeltus fasciatus and the cricket Gryllus bimaculatus. gcl was found to be involved in germ cell development, but not strictly required for germ cell specification, in O. fasciatus, although it appears to function through a mechanism different from that in D. melanogaster. In contrast, no impact was detected on the embryonic germ line upon gcl knockdown in G. bimaculatus. This work serves as a case study into how the roles of genes in the process of germ line development can change over evolutionary time across animals. |
Monday, December 22nd - Stress |
| Couto-Lima, C. A., Saari, S., Garcia, G. S., Rocha, G. H., Ten Hoeve, J., Dufour, E., Oliveira, M. T. (2025). Impairment of Muscle Function Causes Pupal Lethality in Flies Expressing the Mitochondrial Alternative Oxidase. Biomolecules, 15(4) PubMed ID: 40305317
Summary: The mitochondrial alternative oxidase (AOX) from the tunicate Ciona intestinalis has been explored as a potential therapeutic enzyme for human mitochondrial diseases, yet its systemic effects remain poorly understood. This study investigated the metabolic and physiological consequences of AOX expression during the development of Drosophila cultured cells under dietary stress. The combination of strong, ubiquitous AOX expression and a low-nutrient condition leads to pupal lethality and severe defects in larval musculature, characterized by actin aggregation and muscle shortening. These structural abnormalities correlate with a decrease in larval biomass and motility. Interestingly, the muscle defects and the motility impairments vary in severity among individuals, predicting survival rates at the pupal stage. AOX expression in specific tissues (muscle, nervous system or fat body) does not individually recapitulate the lethal phenotype observed with ubiquitous expressions of the enzyme, indicating a complex metabolic imbalance. Metabolomic analysis revealed that the low-nutrient diet and AOX expression have opposite effects on most metabolites analyzed, especially in the levels of amino acids. Notably, supplementation of the low-nutrient diet with the essential amino acids methionine and/or tryptophan partially rescues pupal viability, body size, muscle morphology, and locomotion, whereas supplementation with proline and/or glutamate does not, highlighting a specific perturbation in amino acid metabolism rather than general bioenergetic depletion. These findings demonstrate that AOX expression disrupts metabolic homeostasis, with developmental and physiological consequences that must be considered when evaluating AOX for therapeutic applications. | Knop, M., Treitz, C., Bettendorf, S., Bossen, J., von Frieling, J., Doms, S., Saboukh, A., Bruchhaus, I., Kuhnlein, R. P., Baines, J. F., Tholey, A., Roeder, T. (2025). Mitochondrial sirtuin 4 shapes the intestinal microbiota of Drosophila by controlling lysozyme expression. Anim Microbiome, 7(1):63 PubMed ID: 40514757
Summary: Sirtuins are deacetylases that are highly conserved throughout the animal kingdom. They act as metabolic sensors that coordinate cellular responses, allowing an adapted response to various stressors. Epithelial cells, especially those of the intestine, are directly exposed to a wide range of stressors. Together with the microbiota, they form a complex ecosystem with mutual influences. The significance of sirtuins in this complex system is still waiting to be clarified. This study shows that a protein-restricted diet strongly increases the intestinal expression of sirtuin 4 (dSirt4), the only mitochondrial sirtuin in Drosophila. To elucidate the effects of deregulated dSirt4 expression in the intestine, dSirt4 knockout flies were analyzed. These flies showed substantial changes in their intestinal proteome and physiological properties. One of the most striking effects was the strong induction of lysozymes in the intestine, with a corresponding increase in lysozyme activity. This effect was organ-autonomous, as it was also observed in flies with dSirt4 knocked out only in intestinal enterocytes. The significant increase in lysozyme abundance in response to tissue-specific dSirt4 knockdown did not reduce the total number of bacteria in the intestine. However, it did affect the microbiota composition by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to dSirt4-dependent lysozyme expression, which is absent in a lysozyme-deficient background. dSirt4 knockout in the enterocytes shortened the lifespan of the flies, as did ectopic lysozyme overexpression in the enterocytes. The only mitochondrial sirtuin in Drosophila, dSirt4, is induced by dietary stress in intestinal epithelial cells, which directly regulates the lysozyme activity of these cells. This altered lysozyme activity was associated with a shift in the microbiota composition, demonstrating a direct link between stress, nutrition, and the host's microbiota regulation. |
| Zanco, B., Morimoto, J., Cockerell, F., Mirth, C., Sgro, C. M. (2025). Nutritional optima for life-history traits vary with temperature and across locally-adapted populations. J Insect Physiol, 163:104815 PubMed ID: 40334813
Summary: As the climate changes, populations must overcome more frequent and more extreme exposure to a wide range of stressors. However, knowledge of how locally-adapted populations respond to combinations of stressors remains incomplete. Recent studies show that elevated temperatures can interact with nutrition to accentuate the negative effects of a poor diet, suggesting higher costs of nutritional stress when individuals experience temperatures outside of their locally-adapted conditions. This can translate into reduced nutrient optima under thermal stress in life-history trait landscapes, a hypothesis that remains to be tested. This study used the Geometric Framework for Nutrition to test this hypothesis using two locally-adapted populations of Drosophila melanogaster from opposing ends of a well-characterised adaptive gradient along the east coast of Australia (tropical vs. temperate). The negative effects of nutritional stress were found to be significantly greater in the tropical population under warmer temperatures. In contrast, the temperate population was able to utilise a broader nutritional space to maintain high viability and a large wing size across the range of fluctuating temperatures. These findings reveal the ways in which local adaptation impacts how populations navigate and explore the nutritional space in response to increasingly stressful thermal conditions. These data suggest that certain populations may be better able to cope with increasingly stressful and variable environments, while others may be more vulnerable to local extinctions. | Zhao, Y., Alexandre, C., Kelly, G., Vincent, J. P., Perez-Mockus, G. (2025). HIF-1alpha-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development. Nat Commun, PubMed ID: 41423448
Summary: Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1alpha stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. This expectation that rising levels of HIF-1alpha dampen TOR signalling activity through transcriptional activation of REDD1. Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1alpha levels and activity. Thus, HIF-1alpha mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1alpha knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. It is concluded that Sima/HIF-1alpha prevents TOR-mediated growth from depleting local oxygen supplies during normal development. |
| Paul, B., Merta, H., Ugrankar-Banerjee, R., Hensley, M. R., Tran, S., do Vale, G. D., Zacherias, L., Hewett, C. K., McDonald, J. G., Font-Burgada, J., Mathews, T. P., Farber, S. A., Henne, W. M. (2025). Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis. Dev Cell, PubMed ID: 40318637
Summary: Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, this study characterized the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, this study proposes that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network. | Ghosh, K., Iyer, R. K., Sood, S., Islam, M. S., Labad, J. G., Khadilkar, R. J. (2025). Genetic perturbation of cellular homeostasis regulates integrated stress response signaling to control Drosophila hematopoiesis. Biol Open, 14(7) PubMed ID: 40554752
Summary: Aging results in a decline in cellular and molecular functions. One of the hallmarks of aging is stem cell exhaustion, which impacts self-renewal and differentiation. This study employed the Drosophila larval lymph gland (LG) to investigate the impact of genetic perturbation of cellular homeostasis on hematopoiesis. The LG consists of a posterior signaling center (PSC) - a stem cell niche that maintains medullary zone (MZ) prohemocytes, whereas the cortical zone (CZ) consists of differentiated hemocytes. Over-activation of Toll or Imd pathway were employed to disrupt cellular homeostasis, whereas Foxo or Atg8 were employed to balance it. Genetic perturbation of cellular homeostasis displays hallmarks of aging. Induction of Toll or Imd pathway locally and systemically leads to a decreased niche size and increased differentiation, whereas Foxo or Atg8 over-expression shows an opposite trend. The integrated stress response (ISR) pathway was shown to be induced upon Toll or Imd over-activation and LGs with ISR perturbation show increased hemocyte differentiation. Genetic epistasis shows that ectopic over-expression of ISR components upon Imd activation can rescue hematopoietic defects. Overall, this study explores how genetic perturbation of cellular homeostasis can impact hematopoiesis. This research has implications in understanding how abrogation of cellular homeostatic mechanisms may lead to onset of malignancies. |
Friday, December 19th - Stem Cells |
| Zheng, C., Zheng, J., Wang, X., Zhang, Y., Ma, X., He, L. (2025). Two-pore-domain potassium channel Sandman regulates intestinal stem cell homeostasis and tumorigenesis in Drosophila melanogaster. J Genet Genomics, PubMed ID: 40381822
Summary: Potassium channels regulate diverse biological processes, ranging from cell proliferation to immune responses. However, the functions of potassium homeostasis and its regulatory mechanisms in adult stem cells and tumors remain poorly characterized. This study identified Sandman, a two-pore-domain potassium channel in Drosophila, as an essential regulator for the proliferation of intestinal stem cells and malignant tumors, while dispensable for the normal development processes. Mechanistically, loss of sandman elevates intracellular K(+) concentration, leading to growth inhibition. This phenotype is rescued by pharmacological reduction of intracellular K(+) levels using the K(+) ionophore. Conversely, overexpression of sandman triggers stem cell death in most regions of the midgut, inhibits tumor growth, and induces a Notch loss-of-function phenotype in the posterior midgut. These effects are mediated predominantly via the induction of endoplasmic reticulum (ER) stress, as demonstrated by the complete rescue of phenotypes through the co-expression of Ire1 or Xbp1s. Additionally, human homologs of Sandman demonstrated similar ER stress-inducing capabilities, suggesting an evolutionarily conserved relationship between this channel and ER stress. Together, these findings identify Sandman as a shared regulatory node that governs Drosophila adult stem cell dynamics and tumorigenesis through bioelectric homeostasis, and reveal a link between the two-pore potassium channel and ER stress signaling. | Dominado, N., Ye, R., Casagranda, F., Heaney, J., Siddall, N. A., Abud, H. E., Hime, G. R. (2025). Alternate Grainy head isoforms regulate Drosophila midgut intestinal stem cell differentiation. Cell Death Discov, 11(1):206 PubMed ID: 40295491
Summary: Regeneration of the Drosophila midguta epithelium depends upon differential expression of transcription factors in intestinal stem cells and their progeny. The grainy head locus produces multiple splice forms that result in production of two classes of transcription factors, designated Grh.O and Grh.N. grainy head expression is associated with epithelial tissue and has roles in epidermal development and regeneration but had not been examined for a function in the midgut epithelium. This study shows that null mutant clones had a limited effect on intestinal stem cell (ISC) maintenance and proliferation but surprisingly specific loss of all Grh.O isoforms results in loss of ISCs from the epithelium. This was confirmed by generation of a new Grh.O class mutant to control for genetic background effects. Grh.O mutant ISCs were not lost due to cell death but were forced to differentiate. Ectopic expression of a Grh.N isoform also resulted in ISC differentiation similar to loss of Grh.O function. Grh.O expression must be tightly regulated as high level ectopic expression of a member of this isoform class in enteroblasts, but not ISCs, resulted in cells with confused identity and promoted excess proliferation in the epithelium. Thus, midgut regeneration is not only dependent upon signalling pathways that regulate transcription factor expression, but also upon regulated mRNA splicing of these genes. |
| Raz, A. A., Hassan, H., Yamashita, Y. M. (2025). Modular regulation of the stem cell transcriptome defines self-renewal, differentiation, and dedifferentiation. bioRxiv, PubMed ID: 40321206
Summary: Adult stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. Stem cells themselves are frequently replenished by dedifferentiation of partially differentiated progeny. It is a paradox how stem cells and progeny retain the same potential to be or become stem cells, while undergoing different trajectories of self-renewal, differentiation, and dedifferentiation. This study shows that Drosophila male germline stem cells (GSCs) solve this paradox via two parallel mechanisms. First, differentiating progeny (spermatogonia) may maintain dedifferentiation-competence by inheriting the transcriptome from GSCs in the form of perdurant mRNA, without actively transcribing these genes. Second, two niche signaling pathways (Bmp and Jak-Stat) activate overlapping but distinct subsets of transcriptional targets, and their combinatorial activity allows equally-potent cells to choose different trajectories. Together, this study reveals how a pool of dedifferentiation-competent progeny is maintained to regenerate stem cells as needed without resulting in tumorigenic stem cell overproduction. | Knudsen, C., Moriya, A., Nakato, E., Gulati, R., Akiyama, T., Nakato, H. (2025). Chondroitin sulfate regulates proliferation of Drosophila intestinal stem cells. PLoS Genet, 21(5):e1011686 PubMed ID: 40343906
Summary: The basement membrane (BM) plays critical roles in stem cell maintenance and activity control. This study shows that chondroitin sulfate (CS), a major component of the Drosophila midgut BM, is required for proper control of intestinal stem cells (ISCs). Loss of Chondroitin sulfate synthase (Chsy), a critical CS biosynthetic gene, resulted in elevated levels of ISC proliferation during homeostasis, leading to midgut hyperplasia. Regeneration assays demonstrated that Chsy mutant ISCs failed to properly downregulate mitotic activity at the end of regeneration. CS was also found to be essential for the barrier integrity to prevent leakage of the midgut epithelium. CS is known to be polymerized by the action of the complex of Chsy and another critical protein, Chondroitin polymerizing factor (Chpf). Chpf mutants show increased ISC division during midgut homeostasis and regeneration, similar to Chsy mutants. As Chsy is induced by a tissue damage during regeneration, the data suggest that Chpf functions with Chsy to facilitate CS remodeling and stimulate tissue repair. It is proposed that the completion of the repair of CS-containing BM acts as a prerequisite to properly terminate the regeneration process. |
| Chen, Y., Sun, L. V. (2025). alphaSnap plays a pivotal role in the maintenance of Drosophila ISCs survival and tissue homeostasis. Sci Rep, 15(1):18989 PubMed ID: 40447682
Summary: A genome-wide transgenic RNAi screen in adult Drosophila intestines and identified soluble N-ethylmaleimide-sensitive factor-attachment protein alpha (αSnap), which regulates the survival of intestinal stem cells (ISCs). To further elucidate the function of αSnap in ISC survival, a series of immunofluorescence staining experiments was performed. The results revealed that the ablation of αSnap in ISCs results in cell death through necrosis rather than apoptosis. The absence of αSnap triggers a series of cellular senescence cascades in the Drosophila gut and brain, including lipid droplet (LD) accumulation, the formation of protein aggregates, mitophagy activation, and elevated reactive oxygen species (ROS) levels. Furthermore, the depletion of αSnap in ISCs promotes the expression of Calr, Prtp, LRP1 and Mcr, which might function downstream of αSnap in regulating the survival of ISCs. In addition, this study demonstrated that deficiency of Napa (αSnap homologue in mice) restricts the development of mouse GL261 glioma cell transplantation tumor and induces a senescence cascade in GL261 tumor cells. Overall, these findings indicate that αSnap could serve as a potential therapeutic target for glioma. | Zhang, Y., Ma, P., Wang, S., Chen, S., Deng, H. (2025). Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila. Nat Commun, 16(1):4909 PubMed ID: 40425608
Summary: Breakdown of calcium network is closely associated with cellular aging. Previous work found that cytosolic calcium (CytoCa(2+)) levels were elevated while mitochondrial calcium (MitoCa(2+)) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa(2+) was decoupled from the intracellular calcium network and whether the reduction of MitoCa(2+) drives ISC aging, however, remains unresolved. This study shows that genetically restoring MitoCa(2+) can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa(2+) and Mitochondria-ER contacts (MERCs) form a positive feedback loop via inositol 1,4,5-trisphosphate receptor (IP3R) to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa(2+) reduction and ISC dysfunction in aged flies. These results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases. |
Wednesday, December 17th - Evolution |
| Dewan, N., Kennington, W. J., Tomkins, J. L., Dugand, R. J. (2025). Heroic heirs: evidence for sexy and competitive sons. Evolution, PubMed ID: 40314412
Summary: Leks, a gathering of males to show off their genes without any material benefits to a female, are the quintessential example of female mate choice, yet male-male interactions at leks may predominate. In a lek mating system, males gather at specific arenas to perform elaborate displays, and females visit these sites solely to assess and choose their mates, without receiving any material benefits (such as food, resources, or parental care) from the males. How, and how much, female mate choice versus male-male competition contribute to precopulatory sexual selection, including whether they are aligned or antagonistic, matters to theory and understanding of how selection acts on both males and females. For example, if male-male competition predominates and selection favours harmful, dominant males, then female and population fitness may be compromised. Using Drosophila melanogaster two artificial selection experiments were performed in parallel where selection was altered to favour male-male competition (selection for winners and losers in multi-male competition trials) or female mate choice (selection for winners and losers in single-male latency trials). After seven generations of artificial selection, males from winner-selected lines were more competitive than males from loser-selected lines, regardless of the competitive context in which they were selected. There was also a trend suggesting that males from winner-selected lines were also more attractive. These results support the idea that the outcomes of male-male competition and female choice are aligned, and/or that one process overrides the other. | Hubert, D. L., Arnold, K. R., Greenspan, Z. S., Pupo, A., Robinson, R. D., Chavarin, V. V., Barter, T. T., Djukovic, D., Raftery, D., Vue, Z., Hinton, A., McReynolds, M. R., Harrison, B. R., Phillips, M. A. (2025). Selection for Early Reproduction Leads to Accelerated Aging and Extensive Metabolic Remodeling in Drosophila melanogaster. Genome Biol Evol, 17(5) PubMed ID: 40326415
Summary: Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, understanding of the specific molecular mechanisms underlying these aging patterns remains limited. This study incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster. Specifically, metabolomic change was characterized over the adult lifespan in populations of D. melanogaster where selection for early reproduction has led to an accelerated aging phenotype relative to their controls. Using these data, evolutionary repeatability was evaluated across the metabolome; the value of the metabolome was assessed as a predictor of "biological age" in this system; and specific metabolites associated with accelerated aging were identified. Generally, the findings suggest that selection for early reproduction resulted in highly repeatable alterations to the metabolome and the metabolome itself is a reliable predictor of "biological age". Specifically, clusters of metabolites were found that are associated with the different rates of senescence observed between accelerated aging population and their controls, adding new insights into the metabolites that may be driving the accelerated aging phenotype. |
| Girardeau, A. R., Enochs, G. E., Saltz, J. B. (2025). Evolutionary feedbacks for Drosophila aggression revealed through experimental evolution. Proc Natl Acad Sci U S A, 122(17):e2419068122 PubMed ID: 40273109
Summary: Evolutionary feedbacks occur when evolution in one generation alters the environment experienced by subsequent generations and are an expected result of indirect genetic effects (IGEs). Hypotheses abound for the role of evolutionary feedbacks in climate change, agriculture, community dynamics, population persistence, social interactions, the genetic basis of evolution, and more, but evolutionary feedbacks have rarely been directly measured experimentally, leaving open questions about how feedbacks influence evolution. Using experimental evolution, this study manipulated the social environment in which aggression was expressed and selected in fruit fly (Drosophila melanogaster) populations to allow or limit feedbacks. Selection was carried out for increased male-male aggression while allowing either positive, negative, or no feedbacks, alongside unselected controls. Populations undergoing negative feedbacks had the weakest evolutionary changes in aggression, while populations undergoing positive evolutionary feedbacks evolved supernormal aggression. Further, the underlying social dynamics evolved only in the negative feedbacks treatment. These results demonstrate that IGE-mediated evolutionary feedbacks can alter the rate and pattern of behavioral evolution. | Garlovsky, M. D., Dobler, R., Guo, R., Voigt, S., Dowling, D. K., Reinhardt, K. (2025). Testing for age- and sex- specific mitonuclear epistasis in Drosophila. Evolution 79(8):1568-1582 PubMed ID: 40359151
Summary: The need for efficient ATP production is predicted to result in the evolution of cooperation between the mitochondrial and nuclear encoded components of the electron transport system. Genotypes where mitochondrial and nuclear genomes from different geographic populations are combined (mismatched), are therefore predicted to result in negative fitness consequences. Such negative fitness effects are expected to be prominent in males, since maternal inheritance of mitochondria can lead to accumulation of male-harming mutations (the mother's curse hypothesis), and they may become more prevalent with ageing. To test these predictions, fertility traits of females and males were measured at different ages using a genetically diverse panel of 27 mitonuclear populations of Drosophila melanogaster with matched or experimentally mismatched mitonuclear genomes. No evidence was found that novel mitonuclear combinations had reduced fitness in females. In males, limited evidence was found of mitonuclear interactions affecting fitness in old age, however, not in the direction predicted. Novel mitonuclear combinations were associated with males that sired more offspring. Sex-specific advantages of mismatched males might arise if novel nuclear alleles compensate for deleterious mitochondrial alleles that have accumulated. If such compensatory effects of novel mitonuclear combinations increasing fitness occur in nature, they could represent a possible counterforce to the mother's curse. |
| De Lisle, S. P., Branden, A., Paajarvi Vag, E. (2025). Multivariate sexual selection of color and morphology in a complex trait: the Drosophila wing. Evolution, PubMed ID: 40273310
Identification of traits causally linked to fitness allows for direct tests of the adaptive value of traits. In the case of Drosophila and other insects, wing interference patterns - striking structural color variation generated by optical thin-film interference - have been implicated in mate choice and sexual selection. Yet, it is expected that wing interference patterns may covary with many aspects of wing morphology, such as size and shape. This study used a competitive mating assay in Drosophila melanogaster to assess the degree to which sexual selection acts on wing color independently of wing size and shape. 16% of multivariate wing color, and 17% of corresponding estimated wing thickness, can be explained by wing size and shape. Projection pursuit regression identified three suites of traits - a linear combination of color variables, wing size, and a linear combination of wing shape variables - as the most important predictors of fitness. Analysis of the corresponding selection gradients revealed a combination of strong directional selection on wing size, combined with multivariate stabilizing selection on wing size and shape, with weak but significant directional selection on wing color. These results suggest that sexual selection may act on a complex combination of wing color and morphology in flies. Durr, B. R., Bertolini, E., Takagi, S., Pascual, J., Abuin, L., Lucarelli, G., Benton, R., Auer, T. O. (2025). Olfactory projection neuron rewiring in the brain of an ecological specialist. Cell Rep, 44(5):115615 PubMed ID: 40287940
| Summary: nimal behaviors can differ greatly between closely related species. These behavioral changes are frequently linked to sensory system modifications, but central brain cell-type alterations might also be involved. This study develop advanced genetic tools to compare homologous central neurons in Drosophila sechellia, an ecological specialist, with the generalist Drosophila melanogaster. Through systematic morphological analysis of olfactory projection neurons (PNs), this study revealed that the global anatomy of these second-order neurons is conserved. However, high-resolution, quantitative comparisons identify a striking case of convergent rewiring of PNs in two olfactory pathways critical for D. sechellia's host location. Calcium imaging and labeling of pre-synaptic sites in these evolved D. sechellia PNs indicate that species-specific connections with third-order partners are formed. This work demonstrates that peripheral sensory evolution is accompanied by selective wiring changes in the central brain to facilitate ecological specialization and paves the way to compare other cell types throughout the nervous system. |
Monday, December 15th - Larval and Adult Physiology and Metabolism |
| Brunetti, K., Catalani, E., Del Quondam, S., Romano, N., Ceci, M., Clerici, G., Gordin, M., Bianchini, G., Brandolini, L., Aramini, A., Cervia, D. (2025). A novel free fatty acid receptor agonist improving metabolic health in Drosophila models. Pharmacol Res, 216:107769 PubMed ID: 40348099
Summary: The development of synthetic modulators for human free fatty acid receptors (FFARs) has gained attention for addressing diabetes, metabolic syndrome, and dyslipidaemia. A new dual FFAR1 (GPR40) and FFAR4 (GPR120) agonist, DFL23916, was recently identified to improve glucose homeostasis, prompting investigations into its effects on metabolic disorders. This study assessed the selectivity and toxicity of DFL23916 in vitro and evaluated its effects in vivo using Drosophila melanogaster models of high-sugar (HSD) and high-fat diets (HFD). DFL23916 showed no off-target activities with no toxicity/hepatotoxicity in cultured cells. In adult HSD-fed flies with defective mobility, the oral administration of DFL23916 enhanced climbing speed in a concentration-dependent manner and reduced the high content of glucose and triglyceride levels alongside markers of insulin resistance. The compound did not affect viability and food intake of flies exposed to chronic overcaloric conditions but it inhibited the progressive weight gain. Similarly, larvae development remained unaffected by DFL23916, while it counteracted glucose and triglyceride elevation and reduced lipid droplet size caused by HSD and HFD. Finally, in silico analysis highlighted the relevance of evolutionary conserved Drosophila receptors in fatty acid sensing, suggesting putative candidates for DFL23916 binding. Collectively, these findings indicated the safe profile of DFL23916 and its efficacy in ameliorating hyperglycaemic and hyperlipidaemic features in overcaloric fed flies. These results not only suggest that DFL23916 could be a potential candidate for further investigation in the context of metabolic disorders but also reinforce D. melanogaster as a valuable model for the preclinical evaluation of metabolic interventions, including FFAR-targeting strategies. | Gayer, M. C., Bianchini, M. C., Carrico, M. R. S., Gomes Paz, M. E., Nogueira, C. L., Denardin, E. L. G., Puntel, R. L., Roehrs, R. (2025). Boral 500 SC (sulfentrazone) induces accumulation of heme synthesis intermediates and changes in locomotor behavior and metabolic markers in Drosophila melanogaster. Chemosphere, 380:144468 PubMed ID: 40344814
Summary: Sulfentrazone (SULF) is an herbicide that inhibits protoporphyrinogen oxidase, which is essential for the biosynthesis of chlorophyll and heme. Its prolonged soil half-life, low effective concentration, and the conserved nature of the heme biosynthesis pathway suggest that SULF might significantly affect non-target organisms. This study evaluated the impact of the commercial formulation Boral 500 SC (SULF) on Drosophila melanogaster when exposed to acute concentrations. Fruit flies were exposed to 10-300 mg/L of the herbicide for seven days, which resulted in dose- and time-dependent increases in mortality. Following these results, further evaluations were conducted on flies exposed to 30 and 150 mg/L on the fourth day of treatment. The exposed flies exhibited decreased climbing locomotor capacity (negative geotaxis assay) and reduced exploratory locomotor capacity (open field assay), suggesting an increased energy demand to counteract the herbicide's effects. This was evidenced by decreased weight, reduced energy-rich molecules, and increased total protein levels. Activation of the heme biosynthesis pathway was indicated by the accumulation of protoporphyrin IX, increased total heme in the head, and induction of the porphobilinogen synthase (PBGS) enzyme (&delta-aminolevulinic acid dehydratase, δ-ALA-D, in mammals). Biochemical analysis showed increased thiobarbituric acid reactive species levels and superoxide dismutase (SOD) activity in flies exposed to 150 mg/L, and higher glutathione-S-transferase (GST) activity in the 150 mg/L group. Additionally, there was an increase in MTT reduction assay in flies from the 150 mg/L group. The study highlights that species with significant diurnal activity, such as pollinators, might be especially susceptible to SULF exposure due to accumulated protoporphyrin IX and pro-oxidative activity under light conditions. |
| Hofacker, A. C., Knop, M., Krauss-Etschmann, S., Roeder, T. (2025). Time-Restricted Feeding Promotes Longevity and Gut Health Without Fitness Trade-Offs. Faseb j, 39(10):e70627 PubMed ID: 40364722
Summary: Time-restricted feeding (TRF), a dietary intervention involving daily fasting periods, has been associated with metabolic benefits; however, its long-term physiological impact remains unclear. Using Drosophila melanogaster as a model, this study investigated the effects of a 16:8 TRF regimen on lifespan, reproductive output, gut health, and microbiota composition. TRF significantly extended lifespan, even when applied only during early adulthood. Notably, this longevity benefit occurred without compromising reproductive fitness, as measured by female fecundity in life's most crucial reproductive phase. TRF promoted gut homeostasis in aged flies by reducing intestinal stem cell proliferation and enhancing epithelial barrier integrity. Furthermore, TRF induced a shift in microbiota composition, increasing the prevalence of gram-negative bacterial taxa. These results show that even short-term TRF interventions at a young age can have long-term physiological benefits. Metabolic reprogramming or increased autophagy are the most likely mechanisms mediating the health-promoting effects of this type of nutritional intervention. TRF is an effective, non-invasive strategy for promoting healthy longevity without significant adverse effects on other aspects of life. | Fischer, Z., Nauman, C., Shayestehpour, S., Pence, L., Bouyain, S., Yao, X., Dobens, L. L. (2025). The Drosophila pseudokinase Tribbles translocates to the fat body membrane in response to fasting to modulate insulin sensitivity. Development, 152(8) PubMed ID: 40292740
Summary: The Drosophila pseudokinase Tribbles (Trbl) shares conserved functions with human TRIB3 to bind and inhibit Akt phosphorylation-activation by the Insulin Receptor (InR) to reduce insulin responses; consistent with this, increased levels of human TRIB3 are linked to type 2 diabetes. This study shows that in fat body cells of well-fed Drosophila larvae, Trbl expression is low and predominantly in the nucleus while fasting or genetic reduction of insulin signaling resulted in increased Trbl expression and Trbl protein translocation to the plasma membrane. An E/G mutation in the Trbl pseudokinase kinase activation loop dominantly interfered with Trbl function leading to increased Akt activity, increased stability of Trbl substrates, including Trbl itself, and aberrant redistribution of Trbl multimers to the membrane. Several strategies designed to increase Akt activity were sufficient to translocate Trbl to the membrane, consistent with the notion that subcellular trafficking of Trbl to the fat body cell membrane acts a rheostat to reduce the strength of Akt-mediated insulin responses, counter to the InR, which has been shown to redistribute away from the membrane to modulate insulin signaling. |
| Ozerova, A. M., Kulikova, D. A., Evgen'ev, M. B., Gelfand, M. S. (2025). Temporal Dynamics of Gene Expression During Metamorphosis in Two Distant Drosophila Species. Genome Biol Evol, 17(6) PubMed ID: 40420545
Summary: Complete metamorphosis of holometabolous insects is a complex biological process characterized by profound morphological, physiological, and transcriptional changes. To reveal the temporal dynamics of gene expression during this critical developmental transition, a detailed analysis was conducted of the developmental transcriptomes of two Drosophila species, Drosophila melanogaster and Drosophila virilis. Partial recapitulation of the embryonic transcriptional program was confirmed in pupae, but unlike the traditional hourglass model, suggesting maximal conservation at mid-embryonic stages, at different stages of pupae a more complicated pattern of alternating low and high diversity was observed, resembling an inverted hourglass, or "spindle". This underscores the complexity of developmental processes during complete metamorphosis. Notably, recently formed genes (specific to insects) exhibit pronounced expression peaks during mid-pupal development, indicating their potential role in developmental transitions. | Blandy, A., Hopes, T., Vasconcelos, E. J. R., Turner, A., Fatkhullin, B., Agapiou, M., Fontana, J., Aspden, J. L. (2025). Translational activity of 80S monosomes varies dramatically across different tissues. Nucleic Acids Res, 53(8) PubMed ID: 40331628
Summary: Translational regulation at the stage of initiation can impact the number of ribosomes translating each mRNA molecule. However, the translational activity of single 80S ribosomes (monosomes) on mRNA is less well understood, even though these 80S monosomes represent the dominant ribosomal complexes in vivo. This study used cryo-EM to determine the translational activity of 80S monosomes across different tissues in Drosophila melanogaster. While head and embryo 80S monosomes were found to be highly translationally active, and testis and ovary 80S monosomes were found to be translationally inactive. RNA-Seq analysis of head monosome- and polysome-translated mRNAs, revealed that head 80S monosomes preferentially translate mRNAs with Terminal OligoPyrimidine (TOP) motifs, short 5'-UTRs, short ORFs and are enriched for the presence of uORFs. Overall, these findings highlight that regulation of translation initiation and protein synthesis is mostly performed by monosomes in head and embryo, while polysomes are the main source of protein production in testis and ovary. |
Friday, December 12th - Disease Models |
| Abaquita, T. A. L., Damulewicz, M., Pyza, E. (2025). The neuroprotective role of CncC in a Drosophila model of Parkinson's disease. PLoS One, 20(5):e0322640 PubMed ID: 40359196
Summary: Parkinson's disease (PD) is an incurable neurodegenerative disorder, yet significant advancements have been made in understanding its etiology. Among the risk factors, exposure to neurotoxins plays the greatest role. One of the most dangerous toxins is rotenone, a naturally derived compound that was historically used as an insecticide. This chemical affects mitochondrial function by blocking electron transfer, resulting in increased reactive oxygen species production and accumulation. Recently, the role of the Nrf2 pathway was explored as a possible protective mechanism to minimize the neurotoxic effects leading to Parkinson's disease. This study used Drosophila melanogaster as a model to examine the link between the expression or activity levels of CncC (an ortholog of Nrf2) or HO (an ortholog of HO-1) in the brain and the detrimental effects of chronic exposure to rotenone. Flies with overexpression of CncC or silencing of ho survived better after exposure to rotenone compared with flies with partially suppressed CncC or upregulated ho expression. These experimental groups exposed to rotenone also exhibited significantly fewer degenerated dopaminergic (DA) neurons than did the wild-type group. Nevertheless, only those in which CncC was overexpressed in glia showed the best survival, the greatest percentage of climbing ability, and no effects on DA neurons. These findings were supported by data obtained for flies fed with HO inhibitor (SnPPIX) or activator (hemin), as well as with curcumin (Nrf2 activator). The observed effects were connected with changes in autophagy and apoptosis pathways. These data suggest that possible therapies exploiting Nrf2 activation should include restricting HO upregulation as a neuroprotective strategy against the toxic effects of rotenone. | Alabdi, L., Altuwaijri, N., Zhu, J. Y., Efthymiou, S., Lee, H., Duan, J., Salem, I., Yu, P., Abdullah, N. L., Alzahrani, F., Xu, Q., Felemban, M. M., Alfaifi, A., Rahman, F., Christoforou, M., Maqbool, S., Martinez-Agosto, J. A., Alsaif, H. S., Hashem, M., Helaby, R., Alsulaiman, A., Maroofian, R., Houlden, H., Arold, S. T., Ibrahim, L. A., Han, Z., Alkuraya, F. S. (2025). SLK is mutated in individuals with a neurodevelopmental disorder. EBioMedicine, 116:105725 PubMed ID: 40347834
Summary: Key to neuronal cell polarization and maturation is proper cytoskeletal organization and function that endows the bipolar neuronal cell with mature dendrites, axons, and functional synapses. Ste20-like kinase (SLK) has been shown to have various cytoskeletal roles. SLK regulates the polarity of microtubules, and its deficiency in the developing murine cortex leads to major defects including impaired development of the distal dendritic tree. No neurodevelopmental phenotypes in humans, however, have been linked to SLK. METHODS: Clinical phenotyping, positional mapping, exome sequencing and functional analyses using patient-derived cells, SLK knock down cell lines, as well as a Drosophila model of Slik deficiency (the orthologue of SLK). Three individuals were identified from three families (two are consanguineous) in whom a neurodevelopmental disorder (NDD) is linked to biallelic variants in SLK. The deleterious nature of these variants is confirmed by their failure to rescue the abnormal synapse maturation and locomotor defects phenotype in a Drosophila model of Slik deficiency. This study also recapitulated the previously published abnormal cytoskeletal phenotype using patient cells, which showed abnormal organization of the cytoskeleton with accompanying impairment of migration and polarization. Furthermore, transdifferentiated neurons from patient fibroblasts displayed immature neuronal-like morphology with reduced dendritic arborization. These results support an autosomal recessive SLK-related NDD and suggest abnormal cytoskeleton-mediated neuronal maturation as the underlying mechanism. |
| Abou Daya, F., Mandigo, T., Patel, D., Math, S., Ober, L., Maher, M., Melkani, G., Walker, J., Saxena, R. (2025). Drosophila Modeling Identifies Increased Sleep as a Link Between Insomnia and Cardiovascular Disease. bioRxiv, PubMed ID: 40291700
Summary: Insomnia is a common sleep disorder associated with negative long-term health outcomes. Mendelian randomization studies have found that insomnia significantly increases the risk of cardiovascular disease (CVD). To better understand the link between sleep and heart health, genes associated with both insomnia and CVD were identified. This study modeled the disruption of the Drosophila melanogaster orthologs in neurons and cardiac tissue to characterize their cell-autonomous and non-cell-autonomous role in regulating sleep and cardiac physiology. Three genes were identified that function in neurons and the heart to cell-autonomously regulate the function of each tissue. This study found that the disruption of insomnia- and CVD-associated Drosophila orthologs in the heart most often lead to increased nighttime sleep. Inversely, disruptions in neurons that lead to increased sleep most often result in an elevated heart rate. To confirm the association between increased sleep and cardiac function, a genetic correlation analysis was performed from human data between long sleep-related traits and adverse cardiac outcomes. Significant correlations were found between most long sleep traits and heart failure, coronary artery disease, or myocardial infarction, reinforcing the findings in the fly linking increased or excessive sleep and altered cardiac health. | Tsai, M. H., Lo, C. H., Liu, Y. X., Wu, S. N., Kuo, C. Y., Liu, Y. H., Chang, Y. C., Lin, K. L., Hung, P. C., Chen, H. H., Chen, J. L., Yao, C. K., Hwang, E., Wang, Y. J. (2025). De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy. Hum Mol Genet, PubMed ID: 40472070
Summary: Shaker-type potassium channel genes (Kv1) have been linked to human epilepsies, including KCNA1 (Kv1.1), KCNA2 (Kv1.2), and more recently, KCNA3 (Kv1.3) and KCNA6 (Kv1.6). This study reports three early-onset epilepsy cases with de novo missense mutations in Shaker-type channel genes, including Kv1.3, KCNA4 (Kv1.4), and Kv1.6, identified through whole exome sequencing trio study. The newly identified Kv1.3-V478M, Kv1.6-T421I, and Kv1.4-V558L mutations are located within the channel selectivity filter or S6 hinge, both critical for channel gating. These variants are in paralogous locations of previously reported pathogenic variant in KCNA2. These mutations do not significantly affect trafficking and plasma membrane localization of the Kv channels. In contrast, patch-clamp analysis in a cell-based system reveals that all three mutations cause severe loss-of-function channel properties. Additionally, a Drosophila model highlights the detrimental effects of Kv1.3-V478M on neural circuit activity. Current findings suggest that, similar to Kv1.1, Kv1.2, and Kv1.3, both loss-of-function and gain-of-function mutations in Kv1.6 may contribute to the phenotypic variability in epilepsy severity. This study also extends the list of potassium channel genes implicated in human epilepsy, introducing Kv1.4 as a novel epilepsy-related gene. |
| Gregori, M., Pereira, G. J. S., Allen, R., West, N., Chau, K. Y., Cai, X., Bostock, M. P., Bolsover, S. R., Keller, M., Lee, C. Y., Lei, S. H., Harvey, K., Bracher, F., Grimm, C., Hasan, G., Gegg, M. E., Schapira, A. H. V., Sweeney, S. T., Patel, S. (2025). Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease. J Cell Biol, 224(6) PubMed ID: 40279672
Summary: Parkinson's disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. This study identified novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which lack TPCs, this study showed that the expression of human TPC2 phenocopied LRRK2 G2019S in perturbing dopaminergic-dependent vision and movement in vivo. Mechanistically, dysfunction required an intact pore, correct subcellular targeting and Rab interactivity of TPC2. Reducing Ca2+ permeability with a novel biased TPC2 agonist corrected deviant Ca2+ entry and behavioral defects. Thus, both inhibition and select activation of TPC2 are beneficial. Functional coupling between lysosomal cation release and Ca2+ influx emerges as a potential druggable node in Parkinson's disease. | Buck, S. A., Mabry, S. J., Kunkhyen, T., Yang, Z., Rubin, S. A., Yang, J., Cheetham, C. E. J., Freyberg, Z. (2025). dVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model. Aging Cell:e70096 PubMed ID: 40354193
Summary: Sex differences in Parkinson's disease (PD) offer insights into mechanisms of dopaminergic cell resilience. Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. This study discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the Drosophila model. While aging raised mitochondrial ROS in DA neurons of both sexes, a sexually dimorphic response was observed in the paraquat (PQ) PD model. DA neuron knockdown of the Drosophila vesicular glutamate transporter (dVGLUT) increased mitochondrial ROS only in males, leaving females protected. Cell depolarization, a physiological stressor, similarly raised mitochondrial ROS in DA neurons selectively in males following dVGLUT knockdown. dVGLUT-dependent changes were observed in intracellular ATP in both sexes. Overall, this study discovered sexually dimorphic relationships between dVGLUT, ATP synthesis, and ROS generation in DA neurons, providing a mechanistic basis for DA neuron resilience. |
Thursday, December 11th - Adult physiology and metabolism |
| Nainu, F. D. I., Arsyad, A., Aminuddin, A., Ariyandy, A., Asbah, A., Latada, N. P., Rumata, N. R., Nainu, F. (2025). Impact of Intermittent Fasting on Survival and Gene Expression Profiles Associated with Autophagy, Metabolism, and Antioxidant in Drosophila melanogaster. ACS Omega, 10(19):19636-19642 PubMed ID: 40415793
Summary: Intermittent fasting (IF) has attracted significant interest as a potential approach with promising health benefits, including lifespan extension and metabolic improvement. Previous studies have shown that IF influences autophagy, metabolism, and oxidative stress across various organisms. Drosophila melanogaster was used in this study due to its genetic structure and metabolic responses that closely resemble those of humans, making it a valuable model for studying the effects of IF on cellular and molecular mechanisms. This study investigates the effects of IF on survival and the expression of genes related to autophagy, metabolic, and endogenous antioxidants in D. melanogaster to elucidate the molecular mechanisms underlying these effects. Male w 1118) flies were subjected to either a 4-h or 8-h fasting protocol, three times per week. The results revealed that both fasting protocols improved the survival of flies, with the 8-h IF group showing the most significant benefit (over 60% survival at day 10 compared to ∼50% in the control). Gene expression analysis demonstrated a significant downregulation in the fasting groups, with dilp2 decreasing by 45%, tom40 by 40%, cat by 50%, srl by 35%, and atg8a by 48%, indicating reduced insulin signaling, altered mitochondrial function, decreased antioxidant defense, and suppressed autophagy-related pathways. Notably, these findings contrast with previous studies reporting upregulation of autophagy and antioxidant responses during fasting, suggesting context-dependent regulatory mechanisms. Given the genetic and physiological similarities between D. melanogaster and mammals, these results provide insights into IF-induced metabolic adaptations and their potential implications for longevity and cellular homeostasis. Further research is warranted to clarify the molecular pathways involved. | Liu, J., Zhu, Y., Canic, T., Diaz-Perez, Z., Gultekin, S. H., Zhai, R. G. (2025). Nuclear NAD(+) synthase nicotinamide mononucleotide adenylyltransferase 1 contributes to nuclear atypia and promotes glioma growth. Neurooncol Adv, 7(1):vdaf029 PubMed ID: 40321618
Summary: Glioma is a malignant primary brain tumor with a poor prognosis and short survival. NAD(+) is critical for cancer growth; however, clinical trials targeting NAD(+) biosynthesis had limited success, indicating the need for mechanistic characterization. Nuclear atypia, aberrations in the size and shape of the nucleus, is widely observed in cancer and is often considered a distinctive feature in diagnosis; however, the molecular underpinnings are unclear. High-resolution immunohistochemical analyses was carried outo n glioma tissue samples from 19 patients to analyze the expression of NAD(+) synthase nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and its correlation with nuclear atypia in gliomas. Utilizing a Drosophila model of glial neoplasia, the genetic role of nuclear NMNAT in glioma growth in vivo was investigated, elucidating the cellular mechanisms of NMNAT1 in promoting nuclear atypia and glioma growth. RIn low-grade glioma and glioblastoma, a higher transcription level of NMNAT1 is correlated with poorer disease-free survival. Samples of high-grade gliomas contained a higher percentage of glial cells enriched with NMNAT1 protein. A specific correlation was identified between nuclear NMNAT1 protein level with nuclear atypia. Mechanistic studies in human glioma cell lines and in vivo Drosophila model suggest that NMNAT1 disrupts the integrity of the nuclear lamina by altering the distribution of lamin A/C and promotes glioma growth. This study uncovers a novel functional connection between the NAD(+) metabolic pathway and glioma growth, reveals the contribution of the NAD(+) biosynthetic enzyme NMNAT1 to nuclear atypia, and underscores the role of nuclear NMNAT1 in exacerbating glioma pathology. |
| Pang, L., Wang, D., Liu, H., Zhang, M., Yang, X., Lu, Q., Liu, R. (2025). Antioxidant and anti-aging effect of queen bee larvae (Apis mellifera) protein hydrolysates in Drosophila melanogaster. Int J Biol Macromol, 318(Pt 3):144306 PubMed ID: 40383333
Summary: With increasing concern on the problem of aging, search for food-derived anti-aging compounds has become a hot research area. This study investigated the anti-aging potential and underlying mechanisms of queen bee larvae enzymatic hydrolysates (QBLE) in Drosophila through measurement of the natural lifespan and the mRNA level of related signaling pathways and widely targeted metabolomics analysis based on UPLC-MS/MS. The results showed that QBLE could prolong the mean, median, and maximum lifespan of Drosophila. Particularly, supplementation of QBLE at 5 mg/mL increased the median and mean lifespan by 12.74% and 15.04 %, respectively, indicating that QBLE is effective in prolonging lifespan of Drosophila. Moreover, QBLE supplementation significantly improved the climbing ability and gut integrity, as well as effectively reduced MDA accumulation and increased the levels of CAT, GSH, T-SOD, and T-AOC in aged Drosophila. The effect of QBLE to extend the lifespan was jointly influenced by the intrinsic stress protection system (Nrf2/Keap1), TOR pathway (TOR/S6K, PI3K/Akt/TOR), autophagy-related genes (Atg8a, Atg5), and longevity genes (MTH). Furthermore, differential metabolite analysis revealed that QBLE mitigates Drosophila aging by regulating arginine biosynthesis, glycerophosphlipid metabolism, pyrimidine metabolism, purine metabolism, and cysteine, glycine, and methionine metabolism. Overall, these findings suggest that QBLE has great potential to be applied in the health food and biomedicine fields as a novel protein-derived anti-aging agent. | Ren, M., Chen, S., Greenberg, M. L., Schlame, M. (2025). ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids. Biol Chem, 301(6):110237 PubMed ID: 40378955
Summary: Cardiolipin (CL), the signature phospholipid of mitochondria, carries four fatty acids that are remodeled after de novo synthesis. In yeast, remodeling is accomplished by the joint action of Cld1, a lipase that removes a fatty acid from CL, and Taz1, a transacylase that transfers a fatty acid from another phospholipid to monolysocardiolipin (MLCL). While taz1 homologs have been identified in all eukaryotes, cld1 homologs have remained obscure. This study demonstrates that α/β-hydrolase domain 18 (ABHD18), a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of Abhd18 decreased the concentration of MLCL in murine, Taz-knockout myoblasts. Inactivation of Abhd18 in Drosophila substantially increased the abundance of CL. Abhd18 inactivation also reversed the increase in the rate of CL degradation, as measured with (13)C isotopes, and the accumulation of deacylated CLs, such as MLCL and dilyso-CL, in tafazzin (TAZ)-deficient flies. CL species with more than five double bonds were resistant to ABHD18. These data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. Rather than removing just one fatty acid, this study showed that ABHD18 deacylates CL further. Thus, ABHD18 catalyzes the breakdown of CL, whereas TAZ protects CL from degradation. |
| Liu, Y., Dantas, E., Ferrer, M., Miao, T., Qadiri, M., Liu, Y., Comjean, A., Davidson, E. E., Perrier, T., Ahmed, T., Hu, Y., Goncalves, M. D., Janowitz, T., Perrimon, N. (2025). Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice. Nat Metab, 7(4):823-841 PubMed ID: 40275022
Summary: Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. This study shows that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. This study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression was observed in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer. | Biswas, P., Bako, J. A., Liston, J. B., Yu, H., Wat, L. W., Miller, C. J., Gordon, M. D., Huan, T., Stanley, M., Rideout, E. J. (2025). Insulin/insulin-like growth factor signaling pathway promotes higher fat storage in Drosophila females. bioRxiv, PubMed ID: 40342968
Summary: In Drosophila , adult females store more fat than males. While the mechanisms that restrict body fat in males are becoming clearer, less is known about how females achieve higher fat storage. This study performed a detailed investigation of the mechanisms that promote higher fat storage in females. Intake of dietary sugar supports higher fat storage due to female-biased remodeling of the fat body lipidome. Dietary sugar stimulates a female-specific increase in Drosophila insulin-like peptide 3 (Dilp3), which acts together with greater peripheral insulin sensitivity to augment insulin/insulin-like growth factor signaling pathway (IIS) activity in adult females. Indeed, Dilp3 overexpression prevented the female-biased decrease in body fat after removal of dietary sugar. Given that adult-specific IIS inhibition caused a female-biased decrease in body fat, the data reveal IIS as a key determinant of female fat storage. |
Wednesday, December 10th - Adult neural structure, development and function |
| Andriatsilavo, M., Barata, C., Reifenstein, E., Dumoulin, A., Tao Griffin, T., Dutta, S. B., Stoeckli, E. T., von Kleist, M., Hiesinger, P. R., Hassan, B. A. (2025). Sequential and independent probabilistic events regulate differential axon targeting during development in Drosophila melanogaster. Nat Neurosci, 28(5):998-1011 PubMed ID: 40335773
Summary: Variation in brain wiring contributes to non-heritable behavioral individuality. How and when these individualized wiring patterns emerge and stabilize during development remains unexplored. This study investigated the axon targeting dynamics of Drosophila visual projecting neurons called Dorsal clustered neurons (DCNs/LC14s), using four-dimensional live-imaging, mathematical modeling and experimental validation. Dorsal clustered neurons (DNs) are key groups (DN1s, DN2s, DN3s) within the fly's ~150-neuron circadian clock network, located dorsally in the brain, known for fine-tuning light/temperature responses, linking lateral clock neurons (LNs) to sleep/metabolism circuits, and showing heterogeneity, with some DNs acting as outputs alternative axon targeting choices are driven by a sequence of two independent genetically encoded stochastic processes. Early Notch lateral inhibition segregates DCNs into Notch(ON) proximally targeting axons and Notch(OFF) axons that adopt a bi-potential transitory state. Subsequently, probabilistic accumulation of stable microtubules in a fraction of Notch(OFF) axons leads to distal target innervation, whereas the rest retract to adopt a Notch(ON) target choice. The sequential wiring decisions result in the stochastic selection of different numbers of distally targeting axons in each individual. In summary, this work provides a conceptual and mechanistic framework for the emergence of individually variable, yet robust, circuit diagrams during development. | Barraza, D., Ding, X., Wang, Z., Jugder, B. E., Watnick, P. I. (2025). The Drosophila G protein-coupled receptor, GulpR, is essential for lipid mobilization in response to nutrient-limitation. bioRxiv, PubMed ID: 40313923
Summary: Enteroendocrine cells (EECs) of the intestinal epithelium are major regulators of metabolism and energy homeostasis. This is mainly due to their expression and secretion of enteroendocrine peptides (EEPs). These peptides serve as hormones that control many aspects of metabolic homeostasis including feeding behavior, intestinal contractions, and utilization of energy stores. Regulation of EEP production and release depends largely on EEC-exclusive G protein-coupled receptors (GPCRs) that sense nutrient levels. This study reports the identification of a GPCR expressed principally in EECs, which was named GulpR ( due to its role in the response to nutrient stress. GulpR regulates transcription of the EEP Tachykinin (Tk); both GulpR and Tk are essential for the transcriptional response that promotes survival of nutrient limitation. Infection with V. cholerae also activates transcription of Tk and lipid mobilization genes. While GulpR is required for activation of Tk transcription during infection, Tk does not play a role in regulation of lipid mobilization genes or survival of infection. These findings identify a role for GulpR and Tk in survival of starvation and suggest that, although starvation and infection both require significant mobilization of energy stores, the signal transduction systems that regulate the metabolic response to each are distinct. |
| Fan, Y., Tian, Y., Han, J. (2025). The Glutamate-gated Chloride Channel Facilitates Sleep by Enhancing the Excitability of Two Pairs of Neurons in the Ventral Nerve Cord of Drosophila.. Neurosci Bull, PubMed ID: 40304877
Summary: Sleep, an essential and evolutionarily conserved behavior, is regulated by numerous neurotransmitter systems. In mammals, glutamate serves as the wake-promoting signaling agent, whereas in Drosophila, it functions as the sleep-promoting signal. However, the precise molecular and cellular mechanisms through which glutamate promotes sleep remain elusive. This study reveals that disruption of glutamate signaling significantly diminishes nocturnal sleep, and a neural cell-specific knockdown of the glutamate-gated chloride channel (GluClalpha;) markedly reduces nocturnal sleep. Two pairs of neurons in the ventral nerve cord (VNC) were identified that receive glutamate signaling input, and the GluCl&akogal derived from these neurons is crucial for sleep promotion. Furthermore, GluCl&alph; mediates the glutamate-gated inhibitory input to these VNC neurons, thereby promoting sleep. These findings elucidate that GluClα enhances nocturnal sleep by mediating the glutamate-gated inhibitory input to two pairs of VNC neurons, providing insights into the mechanism of sleep promotion in Drosophila. | Erginkaya, M., Cruz, T., Brotas, M., Marques, A., Steck, K., Nern, A., Torrao, F., Varela, N., Bock, D. D., Reiser, M., Chiappe, M. E. (2025). A competitive disinhibitory network for robust optic flow processing in Drosophila. Nat Neurosci, 28(6):1241-1255 PubMed ID: 40312577
Summary: Many animals navigate using optic flow, detecting rotational image velocity differences between their eyes to adjust direction. Forward locomotion produces strong symmetric translational optic flow that can mask these differences, yet the brain efficiently extracts these binocular asymmetries for course control. In Drosophila melanogaster, monocular horizontal system neurons facilitate detection of binocular asymmetries and contribute to steering. To understand these functions, horizontal system cells' central network was reconstructed using electron microscopy datasets, revealing convergent visual inputs, a recurrent inhibitory middle layer and a divergent output layer projecting to the ventral nerve cord and deeper brain regions. Two-photon imaging, GABA receptor manipulations and modeling, showed that lateral disinhibition reduces the output's translational sensitivity while enhancing its rotational selectivity. Unilateral manipulations confirmed the role of interneurons and descending outputs in steering. These findings establish competitive disinhibition as a key circuit mechanism for detecting rotational motion during translation, supporting navigation in dynamic environments. |
| Clayworth, K. V., Auld, V. J. (2025). Dystroglycan mediates polarized deposition of laminin and axon ensheathment by wrapping glia. Development, 152(10) PubMed ID: 40309933
Summary: The Drosophila peripheral nerve contains multiple layers of glial cells and an overlying extracellular matrix, which together support neuronal survival and function. The innermost glial layer, the wrapping glia (WG), ensheathes axons and facilitates action potential conduction. Recent work has identified involvement of laminin, a heterotrimeric extracellular matrix protein complex in WG development. However, the localization and function of laminin in the WG remains poorly understood. The α subunit, Laminin A (LanA), is dynamically expressed by WG, and loss of LanA results in a reduction in WG-axon contact. The deposition of LanA by WG is concentrated between WG and axons and is deposited preferentially around motor axons versus sensory axons. Crag, a GDP-GTP exchange protein, was identified as a factor that controls LanA deposition. Dystroglycan also controls LanA deposition by the WG, and that both Dystroglycan and Dystrophin are present and necessary for WG ensheathment of axons. Thus, WG contain the highly conserved Dystroglycan/Dystrophin complex, which not only associates with deposited laminin but is necessary for the polarized deposition of laminin and the correct ensheathment of peripheral nerve axons. Summary: | Lee, S. J., Dallmann, C. J., Cook, A., Tuthill, J. C., Agrawal, S. (2025). Divergent neural circuits for proprioceptive and exteroceptive sensing of the Drosophila leg. Nat Commun, 16(1):4105 PubMed ID: 40316553
Somatosensory neurons provide the nervous system with information about mechanical forces originating inside and outside the body. This study uses connectomics from electron microscopy to reconstruct and analyze neural circuits downstream of the largest somatosensory organ in the Drosophila leg, the femoral chordotonal organ (FeCO). The FeCO has been proposed to support both proprioceptive sensing of the fly's femur-tibia joint and exteroceptive sensing of substrate vibrations, but it was unknown which sensory neurons and central circuits contribute to each of these functions. This study found that different subtypes of FeCO sensory neurons feed into distinct proprioceptive and exteroceptive pathways. Position- and movement-encoding FeCO neurons connect to local leg motor control circuits in the ventral nerve cord (VNC), indicating a proprioceptive function. In contrast, signals from the vibration-encoding FeCO neurons are integrated across legs and transmitted to mechanosensory regions in the brain, indicating an exteroceptive function. Overall, these analyses reveal the structure of specialized circuits for processing proprioceptive and exteroceptive signals from the fly leg. These findings are consistent with a growing body of work in invertebrate and vertebrate species demonstrating the existence of specialized limb mechanosensory pathways for sensing external vibrations. |
Monday, December 8th - Gonads |
| Misner, R., Reilein, A., Kalderon, D. (2025). Regulation of somatic stem cell and niche precursor fates and proliferation of by Wnt, JAK-STAT, Hedgehog and Hippo/Yorkie pathways during Drosophila pupal ovary development resembles the signaling framework organizing adult stem cell behavior. bioRxiv, PubMed ID: 40463270
Summary: Follicle Stem Cells (FSCs) in the germarium of a Drosophila melanogaster ovary are maintained through independent regulation of division and differentiation. Adult FSCs can become proliferative Follicle Cells (FCs) to the posterior, or quiescent Escort Cells (ECs) to the anterior. Graded extracellular Hedgehog (Hh) and Wnt signals emanate from cells anterior to FSCs (Cap Cells and ECs) to guide these behaviors together with an inverse JAK-STAT pathway stimulated by ligand from a more posterior source (polar FCs). This study used lineage analyses to investigate the role of those signals in the development of ECs, FSCs and FCs from a common set of precursors during pupation. Previous studies found that the most anterior precursors divide slowest, with quiescence spreading to all future ECs from the anterior, FSCs are specified simply by their location at eclosion, and the first FCs derive from a group of cells that accumulates posterior to the developing germline over the first 48h of pupation. This study now shows that the latter cells derive from migration of precursors out of the developing germarium. Wnt pathway activity favored conversion of precursors to more anterior adult derivatives, while JAK-STAT pathway activity favored posterior outcomes. Wnt pathway activity increased over the first 48h and maintained a graded pattern throughout pupation, terminating at the anterior extent of FC specification, commensurate with Wnt pathway activity continuously opposing FC formation. JAK-STAT pathway activity was consistently lowest in anterior cells, indicating a posterior source early in pupation prior to formation of the first polar FCs. Precursor division was promoted by JAK-STAT signaling and also by Hh signaling, acting through transcriptional induction of yorkie. Faster division favored a precursor becoming an FSC, as seen for FSC lineage maintenance in adults. | McQueen, E., Rice, G., Pillai, S., Ziabari, O. S., Vincent, B. J., Rebeiz, M. (2025). Parallels in the Regulatory Landscape of Dimorphic Female and Male Genital Structures in Drosophila melanogaster. bioRxiv, PubMed ID: 40463176
Summary: Understanding how morphological structures evolve via changes to their development is an ongoing pursuit in biology. Comparative approaches examine changes in the expression or function of key developmental molecules (e.g. transcription factors, signaling molecules or cellular effectors) within homologous structures, and correlate these changes with structural divergence across species, populations, the sexes, or even between different body parts within individuals. The female and male genitalia of Drosophila offer an excellent opportunity to investigate homology and trait evolution, as fruit fly genital structures are developmentally tractable and evolve rapidly. While previous work has characterized gene regulatory networks operating in the development and evolution of male genital structures in Drosophila, female pupal genitalia are comparatively understudied. This study traced the development of female pupal genitalia to determine when and how individual structures form. Then the expression patterns of 29 transcription factors were measured in both female and male genital structures at high resolution using hybridization chain reaction and confocal microscopy. These transcription factors were found to be highly patterned in both sexes, and some serve as marker genes for distinct genital structures in females. These results suggest that the same transcription factors may control developmental processes in female and male genitalia, and this data enables future studies that interrogate how developmental gene regulatory networks specialize and evolve in both sexes. |
| Duncalf, L., Wang, X., Aljabri, A. A., Campbell, A. E., Alharbi, R. Q., Donaldson, I., Hayes, A., Peti, W., Page, R., Bennett, D. (2025). PNUTS:PP1 recruitment to Tox4 regulates chromosomal dispersal in Drosophila germline developmentTitle. Cell Rep, 44(5):115693 PubMed ID: 40347473
Summary: Ser/Thr protein phosphatase 1 (PP1) forms a large nuclear holoenzyme (with PNUTS, WDR82, and Tox4) whose emerging role is to regulate transcription. However, the role of Tox4, and its interplay with the other phosphatase subunits in this complex, is poorly understood. This study combined biochemical, structural, cellular, and in vivo experiments to show that, while tox4 is dispensable for viability, it is essential for fertility, having both PNUTS-dependent and -independent roles in Drosophila germline development. Tox4 requires zinc for PNUTS TFIIS N-terminal domain (TND) binding, and that it binds the TND on a surface distinct from that used by established TND-interacting transcriptional regulators. Selective disruption of the PNUTS-Tox4 and the PNUTS-PP1 interaction is critical for normal gene expression and chromosomal dispersal during oogenesis. Together, these data demonstrate how interactions within the PNUTS-Tox4-PP1 phosphatase combine to tune transcriptional outputs driving developmental transitions. | Zheng, Y., Lee, Y. C., Wang, Y. T., Chiang, P. K., Chang, S. L., Hsu, H. J., Hsu, L. S., Bach, E. A., Tseng, C. Y. (2025). Age-related declines in niche self-renewal factors controls testis aging and spermatogonial stem cell competition through Hairless, Imp, and Chinmo. bioRxiv, PubMed ID: 40370955
Summary: Aging is associated with progressive tissue decline and shifts in stem cell clonality. The role of niche signals in driving these processes remains poorly understood. Using the Drosophila testis, a regulatory axis was Identified in which age-related decline of niche signals (BMPs) lead to upregulation of the co-repressor Hairless, which downregulates the RNA-binding protein Imp in aged germline stem cells (GSCs). Reduced Imp causes loss of Chinmo, a key factor in GSC aging and competition. Reduced Chinmo causes ectopic Perlecan secretion which accumulates in the testis lumen and causes GSC loss. Aging of the testis is reversed by increasing BMPs in the niche, or by overexpressing Imp or depleting Hairless in GSCs. Furthermore, GSC clones with reduced Imp or increased Hairless are more competitive, expelling wild-type neighbors and monopolizing the niche. Thus, BMPs regulate testicular niche aging through the Hairless-Imp-Chinmo axis and "winning" GSCs usurp these aging mechanisms. |
| Xu, D., Pan, J., Zhang, Y., Fang, Y., Zhao, L., Su, Y. (2025). RpS24 Is Required for Meiotic Divisions and Spermatid Differentiation During Drosophila Spermatogenesis. Faseb J, 39(11):e70646 PubMed ID: 40421592
Summary: In Drosophila, testes contain highly heterogeneous ribosome populations. Several ribosomal proteins (RPs) have been shown to play specific and distinct roles during different stages of spermatogenesis. However, the detailed functions and mechanisms of RPs in spermatogenesis remain unclear. This study analyzed the function of RpS24 during Drosophila spermatogenesis. RpS24 is required for sperm production and male fertility of adult flies. Loss of RpS24 causes defects in meiotic chromosome segregation and cytokinesis, failures of spermatid elongation with incomplete axoneme assembly, and twisted mitochondrial derivatives. To trace back the cause of these defects, RpS24 inhibition resulted in the abnormal number and localization of centrosomes in spermatocytes that led to the formation of irregular spindles. During the subsequent elongation process, the centrosome-derived basal body was unable to couple with the nucleus and underwent degradation that impaired microtubule elongation in the RpS24-knockdown spermatid. These findings indicated that RpS24 may play a necessary role in maintaining the structural stability of centrosomes, therefore affecting spindle assembly in spermatocytes and the subsequent basal body formation and function in spermatids, which are essential for meiotic chromosome segregation, cytokinesis, and flagellum elongation in Drosophila testes. | Thomalla, J. M., Giedt, M. S., White, R. P., Wipf, I. J., Shipley, A., Welte, M. A., Tootle, T. L. (2025). The lipid droplet protein Jabba promotes actin remodeling downstream of prostaglandin signaling during Drosophila oogenesis. bioRxiv, PubMed ID: 40463279
Summary: Growing evidence supports that lipid droplets (LDs) are critical for producing high-quality oocytes. However, the functions of LDs during oocyte development remain largely unknown. Using Drosophila oogenesis as a model, previous work discovered the LD-associated Adipose Triglyceride Lipase (ATGL) promotes actin remodeling necessary for oocyte development by providing the substrate for producing lipid signals termed prostaglandins (PGs). This study found that Jabba, a LD-associated protein best known for its role in anchoring other proteins to LDs, also promotes PG-dependent actin remodeling. Overexpression of Jabba results in thickened cortical actin and excessive actin bundles, whereas loss of Jabba results in cortical actin breakdown and severely defective actin bundle formation. Jabba was found to regulate actin remodeling independently of ATGL but in conjunction with PG signaling. These data support that there are two PG signaling pathways that promote actin remodeling: one PG pathway that is dependent on ATGL and the other requires Jabba. Overexpression of Jabba rescues the actin defects when PG signaling is lost. Together these data lead to the model that PGs produced independently of ATGL positively regulate Jabba to promote actin remodeling necessary for follicle morphogenesis and the production of a fertilization competent oocyte. |
Friday, December 5th - Genes and Proteins |
| Roy, M. V., Neal, S. J., Pignoni, F. (2025). The third intracellular loop of Drosophila Lilipod is required for protein function in vivo and can mediate protein-protein interactions in vitro. PLoS One, 20(6):e0325326 PubMed ID: 40465773
Summary: zzThe evolutionarily conserved Lipocalin-Interacting Membrane Receptor (LIMR) family (InterPro: IPR006876) consists of transmembrane (TM) proteins characterized by 9 TM domains (TMDs). Their reported biological functions are diverse and remain poorly understood. Previous work showed that the fly family member Lilipod (Lili) impacts biological processes regulated by the fly BMP/TGF-β ligand Decapentaplegic (Dpp), including germline stem cell self-renewal in the Drosophila ovary, dorsal closure during embryonic development and wing vein formation at the pupal stage. Based on this genetic evidence, Lili directly or indirectly enhances bone morphogenetic protein (BMP) signaling. In the ovary, Lili functions between the activated type I BMP receptor and the SMAD intracellular transducer. To gain insight into Lili function at the cellular and molecular levels, the functional significance of its largest intracellular loop, Intracellular Loop 3 (ICL3) was probed. Through mutational analysis, sequences critical for Lili function in vivo were mapped to the evolutionarily conserved regions of ICL3. Additionally, fly-human chimeric proteins in which Lili ICL3 is replaced with the ICL3 of its human homologs, LMBR1 and LMBR1L, can rescue lili null-mutant phenotypes. Using ICL3 as bait in an unbiased Yeast 2-Hybrid (Y2H) screen, putative interactors, including the BMP signaling cascade components Mad, Sara, Nup93 and Nup358 were identified, and further Y2H analyses identified distinct regions on ICL3 as potentially important for protein binding. Taken together, this work has identified ICL3 as a region that is critical for Lili protein function, most likely via its mediation of protein-protein interactions (PPIs). | Chen, W., Laremore, T. N., Yennawar, N. H., Showalter, S. A. (2025). Phosphorylation modulates secondary structure of intrinsically disorder regions in RNA polymerase II. J Biol Chem, 301(6):108533 PubMed ID: 40273986
Summary: The intrinsically disordered C-terminal domain (CTD) of RNA polymerase II contains tandem repeats with the consensus sequence YSPTSPS and coordinates transcription and cotranscriptional events through dynamic phosphorylation patterns. While it has been long hypothesized that phosphorylation induces structural changes in the CTD, a direct comparison of how different phosphorylation patterns modulate the CTD conformation has been limited. Two distinct phosphorylation patterns were created in an essential Drosophila CTD region with the kinase Dyrk1a: one where Ser2 residues are primarily phosphorylated, mimicking the state near transcription termination, and a hyperphosphorylation state where most Ser2, Ser5, and Thr residues are phosphorylated, expanding on previous work on Ser5 phosphorylation, which mimics early transcription elongation. Using (13)C Direct-Detect NMR, the CTD was shown to tend to form transient beta strands and beta turns, which are altered differently by Ser2 and Ser5 phosphorylation. Small-angle X-ray scattering revealed no significant changes in the CTD global dimensions even at high phosphorylation levels, contradicting the common assumption of phosphorylation-induced chain expansion. These findings support a transient beta model in which unphosphorylated CTD adopts transient beta strands at Ser2 during transcription preinitiation. These transient structures are disrupted by Ser5 phosphorylation in early elongation, and later restored by Ser2 phosphorylation near termination for recruiting beta turn-recognizing termination factors. |
| Sullivan, K. G., Bashaw, G. J. (2025). Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline. Elife, 13 PubMed ID: 40407164
Summary: In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). In Drosophila, Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. This study demonstrates that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midline in vivo. In addition, this study conclusively demonstrates a role for Nedd4 in midline crossing. Genetic analysis shows that nedd4 mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo1 in a PY motif-dependent manner. Finally, genetic evidence is presented that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo1 ubiquitination by Nedd4, ultimately leading to its degradation. | Rickle, A., Sudhakar, K., Booms, A., Stirtz, E., Lempradl, A. (2025). More than meets the eye: mutation of the white gene in Drosophila has broad phenotypic and transcriptomic effects. Genetics, 230(3) PubMed ID: 40380877
Summary: The white gene, one of the most widely used genetic markers in Drosophila research, serves as a standard background mutation for transgene insertions and genetic manipulations. While its primary function involves eye pigmentation, mutations in white have been associated with diverse phenotypic effects, including those related to metabolism, behavior, and stress responses. However, many of the published studies do not account for differences in genetic background, raising concerns about the interpretation of experimental results. To address this, fly lines were generated through 10 generations of backcrossing that are highly genetically similar except at the white locus, minimizing background variation. Given the likely metabolic consequences of white gene deletion and its role in neurotransmitter production, this study focused on behavioral, metabolic, and fitness-related traits and performed transcriptomic analysis on adult fly heads. These findings both confirm and refine previous observations, revealing that some reported effects of white mutation are robust while others likely reflect underlying genetic background differences. These results emphasize the necessity of genetic background control in Drosophila research and warrant caution when using white mutants as a baseline for comparative studies. |
| Blanch, J. R., Woodward, N., Krishnamurthy, M., McVey, M. (2025). A non-tethering role for the Drosophila Pol theta linker domain in promoting damage resolution. Nucleic Acids Res, 53(8) PubMed ID: 40275613
Summary: DNA polymerase theta (Pol Θ) is an error-prone translesion polymerase that becomes crucial for DNA double-strand break repair when cells are deficient in homologous recombination or non-homologous end joining. In some organisms, Pol Θ also promotes tolerance of DNA interstrand crosslinks. Due to its importance in DNA damage tolerance, Pol Θ is an emerging target for treatment of cancer and disease. Prior work has characterized the functions of the Pol Θ helicase-like and polymerase domains, but the roles of the linker domain are largely unknown. This study shows that the Drosophila melanogaster Pol Θ linker domain promotes proper egg development and is required for repair of DNA double-strand breaks and interstrand crosslink tolerance. While a linker domain with scrambled amino acid residues is sufficient for DNA repair, replacement of the linker with part of the Homo sapiens Pol @Theta; linker or a disordered region from the FUS RNA-binding protein does not restore function. These results demonstrate that the linker domain is not simply a random tether between the catalytic domains and suggest that intrinsic amino acid residue properties, rather than protein interaction motifs, are more critical for Pol Θ linker functions in DNA repair. | Pachinger, C., Dobbelaere, J., Rumpf-Kienzl, C., Raina, S., Garcia-Baucells, J., Sarantseva, M., Brauneis, A., Dammermann, A. (2025). A conserved role for centriolar satellites in translation of centrosomal and ciliary proteins. J Cell Biol, 224(8) PubMed ID: 40396915
Summary: Centriolar satellites are cytoplasmic particles found in the vicinity of centrosomes and cilia whose specific functional contribution has long been unclear. This study identified Combover as the Drosophila ortholog of the main scaffolding component of satellites, PCM1 [Pericentrin-like protein (PLP)]. Like PCM1, Combover localizes to cytoplasmic foci containing centrosomal proteins and its depletion or mutation results in centrosomal and ciliary phenotypes. Strikingly, however, the concentration of satellites near centrosomes and cilia is not a conserved feature, nor do Combover foci display directed movement. Proximity interaction analysis revealed not only centrosomal and ciliary proteins, but also RNA-binding proteins and proteins involved in quality control. Further work in Drosophila and vertebrate cells found satellites to be associated with centrosomal and ciliary mRNAs, as well as evidence for protein synthesis occurring directly at satellites. Given that PCM1 depletion does not affect overall protein levels, it is proposed that satellites instead promote the coordinate synthesis of centrosomal and ciliary proteins, thereby facilitating the formation of protein complexes. ` |
Thursday, December 4th - Immune response |
| Toubarro, D., Kenney, E., Heryanto, C., Mallick, S., Simoes, N., Eleftherianos, I. (2025). Heterorhabditis bacteriophora Extracellular Vesicles Alter the Innate Immune Signaling in Drosophila melanogaster. Genes (Basel), 16(6) PubMed ID: 40565505
Summary: Heterorhabditis bacteriophora entomopathogenic nematodes are commonly used in agricultural practices for the biological control of insect pests. These parasites are also used in basic research for unveiling the molecular basis of nematode parasitism in relation to the insect anti-nematode response. H. bacteriophora excreted-secreted products have been shown to reduce the expression of the antimicrobial peptide gene Diptericin in Drosophila melanogaster, which increases fly mortality due to enhanced propagation of the mutualistic bacteria Photorhabdus luminescens. However, the effect of entomopathogenic nematode extracellular vesicles (EVs) on the insect host defense remains unknown. This study injected adult flies with H. bacteriophora EVs and used quantitative RT-PCR together with gene-specific primers to analyze the activity of immune-related signaling pathways. H. bacteriophora EVs were found to be lethal to Drosophila melanogaster, and they downregulate the expression of Attacin, Cecropin, and Prophenoloxidase 3 in adult flies. These findings build on previous knowledge and strengthen the notion that H. bacteriophora entomopathogenic nematodes release a variety of effector molecules to modify the insect's innate immune signaling. This information is important because it contributes toward clarifying the molecular interplay between entomopathogenic nematode components and the host's innate immune system. | Bi, H., Guo, W., Lu, S., Zhang, H., Liu, Y., Lu, Q., Dong, M., Li, S., Feng, C. (2025). Eiger pleiotropically regulates the immunity of Ostrinia furnacalis larvae. Insect Sci, PubMed ID: 40601501
Summary: The tumor necrosis factor (TNF) receptor superfamily is a set of essential inflammatory cytokines. In Drosophila, as a homolog of TNF, Eiger was first identified, which is involved in innate immunity signaling pathways. However, in Lepidoptera, the functions of Eiger and its molecular regulatory mechanisms on immune responses are unknown. In this study, Eiger was cloned from Ostrinia furnacalis. OfEiger has a conserved structural domain of the TNF family. The expression of OfEiger increased with the age of O. furnacalis larvae, and was the highest in the hemocytes. After O. furnacalis larvae were injected with Pseudomonas aeruginosa or Micrococcus luteus, the expression of OfEiger was significantly upregulated. The expression levels of several genes in the immune pathways of O. furnacalis larvae were downregulated at 60 h post-injection of double-stranded Eiger (dsEiger), including IMD, Toll, nitric oxide (NO), and mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, the expression levels of the 4 antimicrobial peptides (AMPs), OfLebocin, OfAttacin, OfGloverin, and OfMoricin, were downregulated. In addition, the phagocytosis of Escherichia coli by hemocytes was reduced in O. furnacalis larvae after dsEiger injection. Injections of P. aeruginosa or M. luteus into O. furnacalis larvae following OfEiger RNA interference reduced the larvae's survival rate and increased the expression levels of OfMyD88 and OfJNK. Still, they suppressed the expression of OfNOS1 and AMP genes and inhibited phenoloxidase (PO) activity in O. furnacalis larvae. In conclusion, OfEiger is a vital insect immune regulator, which synergistically regulates IMD, Toll, NO, and MAPK signaling pathways and adjusts PO activity, cellular immunity, AMPs, and other effectors. |
| Arora, S., Critchley, G., Dekmak, A. S., Miesenbock, G., Kempf, A., Ligoxygakis, P. (2025). Loss of the NF-kappaB negative regulator Pirk in Drosophila links brain and gut immunity to neurodegeneration. Brain Commun, 7(2):fcaf144 PubMed ID: 40599166
Summary: A gut-brain axis influenced by host innate immunity and resident microbiota has been implicated in neurological conditions including Alzheimer's disease. However, the precise connection of innate immunity to Alzheimer's disease remains unclear. Using Pirk, a negative regulator of the IMD/NF-kappaB pathway in Drosophila, the neurological phenotypes induced when genetically predisposing flies to chronically over-active immunity were studied. Pirk mutants exhibited age-dependent neurological phenotypes such as reduced locomotion and altered sleep patterns coupled to an increased number of brain lesions. Gut-specific pirk-RNA interference led to earlier onset of the neurological phenotypes which, alongside changes in intestinal bacteria in pirk mutants, highlighted a potential early role for the intestinal ecosystem in the onset of neurodegeneration. In contrast, glia-specific RNA interference of pirk resulted in late onset of the relevant phenotypes suggesting a later contribution of the nervous system to the underlying neuropathology. Knockout of the antimicrobial peptide (AMP) gene AttacinD or rearing flies in axenic conditions recovered some of the neurological phenotypes, suggesting both chronic AMP gene expression as well as gut bacteria changes as mediators. These results indicate an evolutionarily conserved path to neurodegeneration linked to dysregulated immunity. They also reveal that in this context, age-dependent neurodegeneration can happen in less complex non-vertebrate brains in the absence of beta-amyloid or tau aggregation. | Li, H., Zhao, Q., Xu, J., Li, X., Chen, X., Zhang, Y., Li, H., Zhu, Y., Liu, M., Zhao, L., Hua, D., Zhang, X., Chen, K. (2025). From Biomphalaria glabrata to Drosophila melanogaster and Anopheles gambiae: the diversity and role of FREPs and Dscams in immune response. Front Immunol, 16:1579905 PubMed ID: 40370466
Summary: Fibrinogen-related proteins (FREPs) and Down syndrome cell adhesion molecules (Dscams; see Drosophila Dscam) are important immune-related molecules in invertebrates. Although they are found in different taxonomic groups and possess unique functions, both exhibit high diversity and adaptability. FREPs are characterized by their fibrinogen-related domains and have been primarily studied in mollusks, such as Biomphalaria glabrata. Through mechanisms of diversity generation, such as gene conversion and point mutations, BgFREP plays a critical role in the host's defense against parasites. Dscams are immunoglobulin-like transmembrane proteins, mainly studied in arthropods, such as Drosophila melanogaster and Anopheles gambiae. Through alternative splicing, Dscams generate multiple isoforms that participate in pathogen recognition and the precise wiring of neural circuits. In D. melanogaster, DmDscam plays a role not only in neuronal self-recognition but also in pathogen recognition. In A. gambiae, AgDscam defends against parasite infections, by binding to pathogens and mediating phagocytosis. This paper highlights the key roles of FREPs and Dscams in the immunity of two major invertebrate groups-mollusks and arthropods-and summarizes the main advancements in current research. These studies not only deepen the understanding of invertebrate immune mechanisms but also lay a solid foundation for future exploration of their potential applications in the biomedical field. |
| Wei, Y., Jia, W., Sun, Y., Zhang, T., Miao, H., Wu, Z., Dong, R., Ning, F., Kim, W. J. (2025). Investigating the immunomodulatory effects of honeybee venom peptide apamin in Drosophila platforms. Infect Immun, 93(7):e0013125 PubMed ID: 40470946
Summary: Apamin, an 18-amino-acid honeybee venom peptide, although traditionally recognized for its neurotoxic effects, demonstrates potent antimicrobial properties when genetically expressed in Drosophila. This antimicrobial efficacy is independent of its disulfide bonds and is enhanced when the peptide is membrane-tethered. Apamin selectively inhibits pathogenic bacteria, such as Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, while promoting beneficial bacteria like Lactobacillus plantarum, thereby improving the gut microbiome. This gut-localized antimicrobial activity is associated with increased intestinal stem cell proliferation, midgut acidification, and enteroendocrine cell calcium signaling. Furthermore, apamin's antimicrobial function relies on specific peptidoglycan recognition proteins, particularly PGRP-LA and PGRP-SCs. Apamin expression alone is sufficient to restore the integrity of the gut barrier compromised by stressful conditions. Ultimately, apamin supplementation enhances honeybee gut health in the presence of ingested bacteria. The expression of other honeybee antimicrobial peptides also significantly reduces bacterial infection in flies. Overall, this study provides a comprehensive understanding of honeybee venom peptides and antimicrobial peptides functions, utilizing the Drosophila model system to unravel their mechanisms of action and therapeutic potential. | Chauhan, M., Martinak, P. E., Hollenberg, B. M., Goodman, A. G. (2025). Drosophila melanogaster Toll-9 elicits antiviral immunity against Drosophila C virus. J Virol, 99(6):e0221424 PubMed ID: 40366172
Summary: The Toll pathway plays a pivotal role in innate immune responses against pathogens. The evolutionarily conserved pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), play a crucial role in recognition of pathogen-associated molecular patterns (PAMPs). The Drosophila genome encodes nine Toll receptors that are orthologous to mammalian TLRs. While mammalian TLRs directly recognize PAMPs, most Drosophila Tolls recognize the proteolytically cleaved ligand Spatzle to activate downstream signaling cascades. This study demonstrates that Toll-9 is crucial for antiviral immunity against Drosophila C virus (DCV), a natural pathogen of Drosophila. A transposable element insertion in the Toll-9 gene renders the flies more susceptible to DCV. The stable expression of Toll-9 in Drosophila S2 cells results in increased Dicer2 induction and reduced AKT phosphorylation, collectively establishing an antiviral state that inhibits DCV replication. Toll-9 localizes to endosomes, where it binds viral double-stranded RNA (dsRNA), highlighting its role in detecting viral replication intermediates. Together, these findings identify Toll-9 as a key player in antiviral immunity against DCV infection, acting through its ability to recognize dsRNA and drive Dicer2 expression, along with other AKT-mediated antiviral responses. |
Wednesday, December 3rd - Evolution |
| Yamashita, H., Matsumoto, T., Kawashima, K., Abdulla Daanaa, H. S., Yang, Z., Akashi, H. (2025). Dinucleotide preferences underlie apparent codon preference reversals in the Drosophila melanogaster lineage. Proc Natl Acad Sci U S A, 122(21):e2419696122 PubMed ID: 40402244
Summary: Fine-scale population genetic analyses was used to reveal dynamics among interacting forces that act at synonymous sites and introns among closely related Drosophila species. Synonymous codon usage bias has proven to be well suited for population genetic inference. Under major codon preference (MCP), translationally superior "major" codons confer fitness benefits relative to their less efficiently and/or accurately decoded synonymous counterparts. Codon family and lineage-specific analyses expand on previous findings in the Drosophila simulans lineage; patterns in naturally occurring polymorphism demonstrate fixation biases toward GC-ending codons that are consistent in direction, but heterogeneous in magnitude, among synonymous families. These forces are generally stronger than fixation biases in intron sequences. In contrast, population genetic analyses reveal unexpected evidence of codon preference reversals in the Drosophila melanogaster lineage. Codon family-specific polymorphism patterns support reduced efficacy of natural selection in most synonymous families but indicate reversals of favored states in the four codon families encoded by NAY [The four-codon families (known as 4-fold degenerate families or quartets] encoded by the general mRNA codon sequence NAY (where N is any nucleotide, A is adenine, and Y is a pyrimidine, C or U) are primarily those for the amino acids: alanine, proline, threonine and valine. Accelerated synonymous fixations in favor of NAT (The "NAT" in this context refers to codons ending in A or T) and greater differences for both allele frequencies and fixation rates among X-linked, relative to autosomal, loci bolster support for fitness effect reversals. The specificity of preference reversals to codons whose cognate tRNAs undergo wobble position queuosine modification is intriguing. However, this analyses revealed prevalent dinucleotide preferences for ApT over ApC that act in opposition to GC-favoring forces in both coding and intron regions. Evidence is presented that changes in the relative efficacy of translational selection and dinucleotide preference underlie apparent codon preference reversals. | Antunes, M. A., Grandela, A., Matos, M., Simoes, P. (2025). Long-term evolution experiments fully reveal the potential for thermal adaptation. J Therm Biol, 129:104118 PubMed ID: 40305922
Summary: Evolutionary responses may be crucial in allowing organisms to cope with prolonged effects of climate change. However, a clear understanding of the dynamics of adaptation to warming environments is still lacking. Addressing how reproductive success evolves in such deteriorating environments is extremely relevant, as this trait is constrained at temperatures below critical thermal limits. Experimental evolution under a warming environment can elucidate the potential of populations to respond to rapid environmental changes. The few studies following such framework lack analysis of long-term response. This study focused on the long-term thermal evolution of two Drosophila subobscura populations, from different European latitudes, under warming temperatures.Reproductive success of these populations was tested in the ancestral (control) and warming environment after ~50 generations of thermal evolution. A general adaptive response was found to warming temperatures in the long term, since populations evolving in the warming environment showed increased performance in that environment relative to the respective control populations. On the other hand, no clear response was observed in the ancestral environment. Coupled with data from previous generations, this study highlighted a slow pace of adaptive response and differences in that response between populations of distinct histories. These findings demonstrate the need of long-term evolution experiments to fully reveal the potential for thermal adaptation. It also highlights that the scrutiny of different populations is needed as a measure of variation in evolutionary responses within a species. Accounting for these sources of variation - both temporal and spatial - will allow for more robust assessments of climate change evolutionary responses. |
| Mullinax, S. R., Darby, A. M., Gupta, A., Chan, P., Smith, B. R., Unckless, R. L. (2025). A suite of selective pressures supports the maintenance of alleles of a Drosophila immune peptide. Elife, 12 PubMed ID: 40445192
Summary: The innate immune system provides hosts with a crucial first line of defense against pathogens. While immune genes are often among the fastest evolving genes in the genome, in Drosophila, antimicrobial peptides (AMPs) are notable exceptions. Instead, AMPs may be under balancing selection, such that over evolutionary timescales, multiple alleles are maintained in populations. This study, focused on the Drosophila AMP Diptericin A, which has a segregating amino acid polymorphism associated with differential survival after infection with the Gram-negative bacteria Providencia rettgeri. Diptericin A also helps control opportunistic gut infections by common Drosophila gut microbes, especially those of Lactobacillus plantarum. In addition to genotypic effects on gut immunity, strong sex-specific effects were seen that are most prominent in flies without functional diptericin A. To further characterize differences in microbiomes between different diptericin genotypes, 16S metagenomics was used to look at the microbiome composition. Both lab-reared and wild-caught flies were used for sequencing and overall composition as well as the differential abundance of individual bacterial families were looked at. Overall, flies were found that are homozygous for one allele of diptericin A are better equipped to survive a systemic infection from P. rettgeri, but in general have a shorter lifespans after being fed common gut commensals. These results suggest a possible mechanism for the maintenance of genetic variation of diptericin A through the complex interactions of sex, systemic immunity, and the maintenance of the gut microbiome. | Thorholludottir, D. A. V., Hsu, S. K., Barghi, N., Mallard, F., Nolte, V., Schlotterer, C. (2025). Reduced Parallel Gene Expression Evolution With Increasing Genetic Divergence-A Hallmark of Polygenic Adaptation. Mol Ecol, 34(12):e17803 PubMed ID: 40377062
Summary: Parallel evolution, the repeated evolution of similar traits in independent lineages, is a topic of considerable interest in evolutionary biology. Although previous studies have focused on the parallelism of phenotypic traits and their underlying genetic basis, the extent of parallelism at the level of gene expression across different levels of genetic divergence is not yet fully understood. This study investigates the evolution of gene expression in replicate Drosophila populations exposed to the same novel environment at three divergence levels: within a population, between populations and between species. Adaptive gene expression changes are more heterogeneous with increasing genetic divergence between the compared groups. This finding suggests that the adaptive architecture-comprising factors such as allele frequencies and the effect size of contributing loci-becomes more distinct with increasing divergence. As a result, this leads to a reduction in parallel gene expression evolution. This result implies that redundancy is a crucial factor in both genetic selection responses and gene expression evolution. Hence, these findings are consistent with the omnigenic model, which posits that selection acts on higher-order phenotypes. This work contributes to understanding of phenotypic evolution and the complex interplay between genomic and molecular responses. |
| Bullo, E., Chen, P., Fiala, I., Smykal, V., Dolezel, D. (2025). Coevolution of Drosophila-type timeless with partner clock proteins. iScience, 28(5):112338 PubMed ID: 40322083
Summary: Drosophila-type timeless (dTIM) is a key clock protein in fruit flies, regulating rhythmicity and light-mediated entrainment. However, functional experiments indicate that its contribution to the clock differs in various insects. Therefore, a comprehensive phylogenetic analysis was conducted of dTIM across animals and dated its origin, gene duplications, and losses. Variable and conserved protein domains were found, and animal lineages were pinpointed that underwent the biggest changes in dTIM. While dTIM modifications are only mildly affected by changes in the PER protein, even the complete loss of PER in echinoderms had no impact on dTIM. However, changes in dTIM always co-occur with the loss of CRYPTOCHROMES or JETLAG. This is exemplified by the remarkably accelerated evolution of dTIM in phylloxera and aphids. Finally, alternative d-tim splicing, characteristic of Drosophila melanogaster temperature-dependent function, is conserved to some extent in Diptera, albeit with unique alterations. Altogether, this study pinpoints major changes that shaped dTIM evolution. | Thompson, A., May, M. R., Hopkins, B. R., Riedl, N., Barmina, O., Liebeskind, B. J., Zhao, L., Begun, D., Kopp, A. (2025). Quantifying Transcriptome Turnover on Phylogenies by Modeling Gene Expression as a Binary Trait. Mol Biol Evol, 42(5) PubMed ID: 40423579
Summary: Changes in gene expression are a key driver of phenotypic evolution, leading to a persistent interest in the evolution of transcriptomes. Traditionally, gene expression is modeled as a continuous trait, leaving qualitative transitions largely unexplored. This paper details the development of new Bayesian inference techniques to study the evolutionary turnover of organ-specific transcriptomes, which was define as instances where orthologous genes gain or lose expression in a particular organ. To test these techniques, the transcriptomes of 2 male reproductive organs, testes and accessory glands, across 11 species of the Drosophila melanogaster species group. Gene expression states were descretize by estimating the probability that each gene is expressed in each organ and species. Then a phylogenetic model of correlated transcriptome evolution were defined in 2 or more organs and fit it to the expression state data. Inferences under this model imply that many genes have gained and lost expression in each organ, and that the 2 organs experienced accelerated transcriptome turnover on different branches of the Drosophila phylogeny. |
Tuesday, December 2nd - Tumors, Cancer, and Growth |
| Mim, M. S., Cini, S., Frank, C., Wang, Z., Dowling, A., Zartman, J. J. (2025). Forward Engineering Organ Development and Cancer Therapeutics with Optogenetics. bioRxiv, PubMed ID: 40475478
Summary: Robust growth control is an essential requirement for the survival of living organisms, while its dysregulation results in diseases such as cancer. However, a significant knowledge gap exists in understanding how precise organ growth control is achieved. The growing arsenal of optogenetic toolkits allows precise, noninvasive control of cellular signaling in vivo, enabling research into how bioelectrical and chemical cues regulate organ growth. The red-light-activated channelrhodopsin, CsChrimson, was used to stimulate intracellular calcium signaling dynamics in the wing epithelium of Drosophila melanogaster , an established model system for investigating organ size control. By varying light intensity and activation dynamics systematically, a biphasic regulation of final organ size was identified. Illumination of CsChrimson depolarizes cells and stimulates spikes of cytosolic calcium concentrations, a phenomenon explained by a computational model that incorporates the inclusion of both gap junction closure and voltage-gated calcium channel activation. This calcium regulation tunes downstream effectors involved in growth regulation and apoptosis. In particular, prolonged bright red light exposure (100 lux/12 hours) increased cell death in wing imaginal discs and caused severe morphological abnormalities in adult wings, with phenotypic severity dependent on stimulation parameters defined by illumination intensity and period of activation. Strikingly, an optimum level of dim, pulsatile light (5 lux, 1 minute on/off pulse train) resulted in overgrown organs and significantly upregulated cell proliferation. An oncogene, Ras (V12), was overexppressed with CsChrimson; experimental optical simulation parameters can be exploited to control the morphology of tumorous tissues and initiate targeted remission of tumorous growth. These findings and approach provide a powerful framework to dissect the role of dynamic physiological signaling events in organogenesis and offer translational insights into new therapeutic strategies with applications in cancer and regenerative medicine. | Rai, M., Okah, P., Shefali, S. A., Fitt, A. J., Shen, M. Z., Molomjamts, M., Pepin, R., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster. G3 (Bethesda), PubMed ID: 40489577
Summary: D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from α-ketoglutarate (αKG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, two novel loss-of-function mutations were generated in the Drosophila melanogaster gene D2hgdh and these alleles result in ectopic D-2HG. Moreover, it was observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, these efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology. |
| Brutscher, F., Germani, F., Hausmann, G., Jutz, L., Basler, K. (2025). Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras. PLoS Biol, 23(4):e3003068 PubMed ID: 40294154
Summary: Innate immunity in Drosophila acts as an organismal surveillance system for external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. This study used a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In the absence of oncogenic Ras (RasV12), Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, This study showed that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce tumorous overgrowth. | Singh, J., Srikrishna, S. (2025). Scribble knockdown induced metastasis, identification of its associated novel molecular candidates through proteome studies. Biochem Biophys Res Commun, 769:151999 PubMed ID: 40367906
Summary: Loss of function of Scribble, a cell polarity regulator and tumor suppressor gene, is associated with many forms of human cancers but its role in cell proliferation and metastasis remains unknown. This study generated metastatic cancer condition in Drosophila using UAS(RNAi)-GAL4 system by knockdown of Scribble in the wing imaginal discs and tracked metastasis events from early to late pupae (0hr-84 h s) using fluorescence microscopy. The knockdown of Scribble alone leads to the development of primary tumor in the wing imaginal discs, which is capable of establishing metastasis. MMP1, a metastasis biomarker, levels were assessed during pre-and post-metastatic phases in pupae using qRT-PCR and Western blot analysis. Further, the proteome of Scribble knockdown induced tumor-bearing pupae was analyzed by 2-D gel electrophoresis followed by MALDI-TOF MS to identify some novel proteins possibly involved in the progression of tumorigenesis and metastasis events. Six differentially expressed proteins, Obp 99b, Fer2LCH,CG13492, Hsp23, Ubiquitin and Colt, were identified in Scrib knockdown pupae and validated their expression using qRT-PCR. These results suggested that loss of Scrib alone capable of causing metastasis, without the need for cooperative interaction with oncogenic Ras. The newly identified proteins could be important candidates for biomarker/therapeutic target against Scrib associated metastatic cancers. |
| Panagi, M., Galaras, A., Hatzis, P., Apidianakis, Y. (2025). A feed-forward loop between Toll/NF-kappaB and Rac1 promotes epithelial to mesenchymal transition of Ras-oncogenic hindgut enterocytes in Drosophila.. Biol Open, 14(6) PubMed ID: 40476337
Summary: Cancer cell invasion and subsequent metastasis account for most cancer related deaths. However, despite recent progress, there is a need to understand how the main pathways involved in oncogenic cell invasion and metastasis amalgamate into multifunctional networks. Using functional transcriptomic analysis of Drosophila Ras oncogenic hindgut enterocytes, a feed-forward loop was identified between the archetypical Toll/NF-kappaB pathway and Rac1 signalling driving actin cytoskeleton rearrangements, basement membrane degradation, and loss of intercellular adhesion. These data support a signalling network in which Rac1, Toll and JNK signalling transmit the RasV12 signal that primes the hindgut enterocytes towards delamination and dissemination. Rac1 induces actin cytoskeleton signalling genes, Rok, sqh, Apr2, and Apr3, while JNK induces matrix metalloprotease-mediated basement membrane degradation and Toll induces snail-depended E-cadherin repression. Moreover, the Toll pathway positively regulates itself and the Rac1 pathway cytoskeletal genes downstream of the Ras oncogene, but JNK signalling alone does not suffice to induce cell dissemination. Notably, there is a tight crosstalk between Toll and Rac1 signalling that suffices to induce hindgut enterocyte invasiveness and has the key role in transmitting the RasV12 signal. | Paglia, S., Morciano, P., de Biase, D., Giorgi, F. M., Pession, A., Grifoni, D. (2025). Transcriptome-Wide Analysis of Brain Cancer Initiated by Polarity Disruption in Drosophila Type II Neuroblasts. Int J Mol Sci, 26(11) PubMed ID: 40507925
Summary: Brain tumors, in particular gliomas and glioblastoma multiforme (GBM), are thought to originate from different cells facing specific founding insults, a feature that partly justifies the complexity and heterogeneity of these severe forms of cancer. However, gliomas and GBM are usually reproduced in animal models by inducing molecular alterations in mature glial cells, which, though being part of the puzzle, do not represent the whole picture. To fill this conceptual gap, a neurogenic model of brain cancer in Drosophila was developed, demonstrating that the loss of cell polarity in neural stem cells (called neuroblasts in the fruit fly) is sufficient to promote the formation of malignant masses that continue to grow in the adult, displaying several phenotypic traits typical of human GBM. This study expanded on previous work by restricting polarity disruption to Drosophila type II neuroblasts, whose self-renewal is comparable to that of mammalian neural progenitors, with the aim to capture the molecular signature of the resulting cancers in a specific and reproducible context. A comparison of the most deregulated transcripts with those found in human primary GBMs confirmed that this model can be proficiently used to delve into the roots of human brain tumorigenesis. |
Monday, December 1st - Disease Models |
| Kassel, S., Yuan, K., Bunnag, N., Neitzel, L. R., Lu, W., Schwarzkopf, A., Maines, B., ..., Kettenbach, A. N., Robbins, D. J., Ahmed, Y., Lee, E. (2025). The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling. Nat Commun, 16(1):5248 PubMed ID: 40473626
Summary: SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes displace nucleosomes to promote the access of transcription factors to enhancers and promoters. Despite the critical roles of SWI/SNF in animal development and tumorigenesis, how signaling pathways recruit SWI/SNF complexes to their target genes is unclear. This study demonstrates that target gene activation mediated by β-catenin, the essential transcriptional coactivator in the Wnt signal transduction pathway, requires ubiquitylation of the SWI/SNF component Brahma-related gene-1 (BRG1) by the E3 ubiquitin ligase Thyroid Hormone Receptor Interactor 12 (TRIP12). TRIP12 depletion in Drosophila, zebrafish, mouse organoids, and human cells attenuates Wnt signaling. Genetic epistasis experiments place TRIP12 activity downstream of the β-catenin destruction complex. TRIP12 interacts with and ubiquitylates BRG1, and BRG1 depletion blocks TRIP12-mediated Wnt pathway activation. TRIP12 promotes BRG1 binding to β-catenin in the presence of Wnt. These findings support a model in which TRIP12 ubiquitylates BRG1 in the presence of Wnt and promotes its interaction with β-catenin in the nucleus, in order to recruit SWI/SNF to Wnt target genes. These studies suggest a general mechanism by which cell signaling induces the interaction between BRG1 and pathway-specific transcription factors to recruit SWI/SNF complexes to their appropriate target genes. | Dong, P., Li, Y., Wang, Y., Zhao, Q., Lu, T., Chen, J., Guo, T., Ma, J., Yang, B., Wu, H., Huang, H. (2025). Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila. Elife, 13 PubMed ID: 40485562
Summary: Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the fibroblast growth factor mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. This study shows that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. The fat body-derived cytokine, Upd2, was identifed in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. Evidence is provided that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. This study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes. |
| Shodja, D. N., Glassford, W. J., Rice, G., Smith, S. J., Rebeiz, M. (2025). A Notch signal required for a morphological novelty in Drosophila has antecedent functions in genital disc eversion. bioRxiv, PubMed ID: 40463012
Summary: The origin of morphological novelties has long fascinated biologists. Signaling pathways play important roles in the formation of novelties, however, the history of how they become integrated into new developmental programs remains unclear. This study investigated the evolution of the posterior lobe, a novel structure in the male genitalia of Drosophila melanogaster. A Notch signaling center is shown to be required for the formation of this novelty, and ienhancers of the ligand Delta, were identified which allowed tracking the evolutionary history of this signaling center. Surprisingly, it was found that the posterior lobe signaling center emerged from a pre-existing role in genital disc eversion. A likely mechanism is provided by which Delta contributes to genital eversion through a network of apical extracellular matrix, which also became integrated into the posterior lobe program. This work demonstrates that novelties may be formed in the context of already complex developmental processes, by appending new roles to pre-existing signals. | Julick, C. R., Thanintorn, N., Zhang, H., Tsatskis, Y., Glaeser, M., Qu, Y., Rusch, J., McNeill, H. (2025). Regulation of Hippo signaling and planar cell polarity via distinct regions of the Fat intracellular domain. Development, 152(11) PubMed ID: 40377178
Summary: The large Drosophila protocadherin Fat (Ft) is a receptor for signal transduction pathways that control growth (Hippo signaling), planar cell polarity (PCP), metabolism and the proximodistal patterning of appendages. The intracellular domain (ICD) of Ft is crucial in implementing its biological functions. Six regions of high conservation (named A-F) within the ICD have been identified, as well as distinct regions mediating Hippo pathway activity that have been functionally characterized via transgenic expression rescue assays. This study made targeted deletions of these highly conserved residues and the putative Hippo- and PCP-regulating domains of endogenous Ft using CRISPR/Cas9. Through transcriptomic, developmental and phenotypic analyses, this study showed that different regions of Ft contribute uniquely to chromatin dynamics, tissue morphogenesis, PCP and metabolic regulation. This study also demonstrated that different regions of Ft regulate growth in opposite directions, with regions B and F promoting growth and region D inhibiting growth. Strikingly, conserved regions D and F are key regulators of the function of Ft in Hippo activity - exhibiting opposing effects on Hippo pathway modulation - and of the conserved regions, and D is the main regulator of PCP. |
| Liu, X., Montemurro, M., Vanzo, N., Crozatier, M. (2025). Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis. Nat Commun, 16(1):5152 PubMed ID: 40461546
Summary: In adult mammals, hematopoietic stem/progenitor cells reside in the bone marrow, in a specialized microenvironment called a "niche", which is composed of different cell types, including nerves. Although it is established that sympathetic nerves regulate hematopoiesis, little is known about the role of neural serotonin in bone marrow. The Drosophila hematopoietic organ, the lymph gland, is aligned along the aorta, which corresponds to the vascular niche. Serotonin signaling in the vascular niche regulates the hematopoietic response to an immune challenge. The serotonin receptor 1B expressed in vascular niche cells, together with serotonin produced by neurons regulate the degradation of the extracellular matrix of the lymph gland and prevent its premature dispersal after an immune challenge. Serotonin signaling in aorta cells acts via JAK/STAT pathway activation. These results provide novel insights into how vascular niche cells integrate neural information to regulate lymph gland immune stress hematopoiesis. | Wolfstetter, G., Masudi, T., Uçkun, E., Zhu, J. Y., Yi, M., Anthonydhason, V., Guan, J., Sonnenberg, H., Han, Z., Palmer, R. H. (2025). Alk(Tango) reveals a role for Jeb/Alk signaling in the Drosophila heart. Cell Commun Signal, 23(1):229 PubMed ID: 40382638
Summary: Anaplastic lymphoma kinase (Alk) signaling is important in a variety of biological contexts such as cell type specification, regulation of metabolic and endocrine programs, behavior, and cancer. In this work, a Tango GPCR assay-based, dimerization-sensitive Alk activity reporter (Alk(Tango)) was created and receptor activation was followed throughout Drosophila development. Alk(Tango) reports Alk activation in embryonic and larval tissues previously linked to Alk signaling. Remarkably, Alk(Tango) was active in the heartjeb expression in pericardial cells coincided with Alk(Tango) activity. Perturbation of cardiac Alk signaling leads to decreased adult survival as well as lower fitness and increased lethality in response to heat stress. In keeping with a role for Alk, heart measurements reveal arrythmia and irregular muscle contraction upon ligand stimulation. Finally, activation of cardiac Alk signaling induces hyperplasia in the accessory wing hearts of adult flies. |
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