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Current papers in developmental biology and gene function
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May 2026 April 2026 March 2026 February 2026 January 2026 December 2025 November 2025 October 2025 September 2025 August2025 July 2025 June2025 June2025 May 2025 April 2025 March 2025 February 2025 January 2025 December 2024 November 2024 October 2024 September 2024 August 2024 July 2024 June 2024 May 2024 April 2024 March 2024 February 2024 January 2024 December 2022 December 2021 December 2020 December 2019 | Umargamwala, R., Nicolson, S., Manning, J., Carosi, J. M., Kumar, S., Denton, D. (2025). Identification of new candidates regulating autophagy-dependent midgut degradation in Drosophila melanogaster. Cell Death Discov, 11(1):181 PubMed ID: 40240351
Summary: Autophagy-dependent cell death (ADCD) is a context-specific form of programmed cell death that plays an important role in development and homeostasis. During Drosophila metamorphosis, hormonal cues modulate growth and other signalling cascades which results in autophagy-dependent degradation of the obsolete larval midgut. While this process does not require caspase activity or apoptotic machinery, several canonical autophagy-related proteins are also dispensable, suggesting additional regulators may be involved in effectively eliminating the larval midgut. Ubiquitination, a process that attaches one or more ubiquitin moieties to a substrate through sequential reactions involving a cascade of enzymes, plays a critical role in autophagy. As the specific role(s) of ubiquitination in ADCD has not been explored, a RNAi-mediated knockdown screen of over 250 ubiquitin machinery genes was performed in GFP-labelled Drosophila larval midguts and 18 candidate regulators of midgut degradation were identified. This work screened for a role in autophagy-dependent midgut degradation by analysing mosaic clones and genetic interactions with Atg1. Validation and further studies into the ubiquitin conjugating enzyme, Effete (Eff), and two ubiquitin ligases, Cullin-4 (Cul4) and Supernumerary limbs (Slmb), demonstrated interplay between ubiquitination and the autophagy machinery in coordinating autophagy-dependent midgut degradation. | Klemm, J. W., Van Hazel, C., Harris, R. E. (2025). Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity. Elife, 13 PubMed ID: 40042383
Summary: Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, understanding of necrosis and how it impacts surrounding healthy tissue - an essential consideration when developing effective methods to treat such injuries - has been limited by a lack of robust genetically tractable models. Previous work established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. This study further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage. |
| Xu, M., Li, W., Xu, R., Liu, L., Wu, Z., Li, W., Ma, C., Xue, L. (2025). Gp93 safeguards tissue homeostasis by preventing ROS-JNK-mediated apoptosis. Redox Biol, 81:103537 PubMed ID: 39965405
Summary: Reactive oxygen species (ROS) play a pivotal role in maintaining tissue homeostasis, yet their overabundance can impair normal cellular functions, induce cell death, and potentially lead to neurodegenerative disorders. This study identifies Drosophila Glycoprotein 93 (Gp93) as a crucial factor that safeguards tissue homeostasis and preserves normal neuronal functions by preventing ROS-induced, JNK-dependent apoptotic cell death. Firstly, loss of Gp93 induces NK-dependent apoptosis primarily through the induction of ROS. Secondary, neuro-specific depletion of Gp93 results in ROS-JNK-mediated neurodegeneration. Thirdly, overexpression of Gp93 effectively curtails oxidative stress and neurodegeneration caused by paraquat exposure or the aging process. Furthermore, these functions of Gp93 can be substituted by its human ortholog, HSP90B1. Lastly, depletion of HSP90B1 in cultured human cells triggers ROS production, JNK activation, and apoptosis. Thus, this study not only unveils a novel physiological function of Gp93, but also provides valuable insights for understanding the physiological and pathological functions of human HSP90B1. | Korner, M. B., Velluva, A., Bundalian, L., Krohn, K., Schon, K., Schumann, I., Kromp, J., Thum, A. S., Garten, A., Hentschel, J., Abou Jamra, R., Mrestani, A., Scholz, N., Langenhan, T., Le Duc, D. (2025). Drosophila WDFY3/Bchs overexpression impairs neural function. J Neurogenet, 39(1):23-38 PubMed ID: 40000652
Summary: Pathogenic variants in WDFY3, a gene encoding for an autophagy adaptor termed ALFY, are linked to neurodevelopmental delay and altered brain size in human probands. While the role of WDFY3 loss-of-function is extensively studied in neurons, little is known about the effects of WDFY3 upregulation in different cell types of the central nervous system (CNS). This study shows that overexpression of the Drosophila melanogaster WDFY3 ortholog, Bchs, in either glia or neurons impaired autophagy and locomotion. Bchs glial overexpression also increased VNC size and glial nuclei number significantly, whereas neuronal Bchs overexpression affected wing and thorax morphology. 79 genes were identified that were differentially expressed and overlapped in flies that overexpress Bchs in glial and neuronal cells, respectively. Additionally, upon neuronal Bchs overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondrial function. These data indicate that glial as well as neuronal Bchs upregulation can have detrimental outcomes on neural function. |
| Hilu-Dadia, R., Ghanem, A., Vogelesang, S., Ayoub, M., Hakim-Mishnaevski, K., Kurant, E. (2025). Santa-maria is a glial phagocytic receptor that acts with SIMU to recognize and engulf apoptotic neurons. Cell reports, 44(1):115201 PubMed ID: 39799566
Summary: The elimination of superfluous neurons via apoptosis and subsequent glial phagocytosis is crucial for the development of the central nervous system (CNS). In Drosophila, two glial phagocytic receptors, six-microns-under (SIMU) and Draper, mediate the phagocytosis of apoptotic neurons during embryogenesis. However, in simu;draper double-mutant embryos, some apoptotic neurons are still engulfed by the glia, suggesting the involvement of additional receptors. This study discovered the Drosophila CD36 homolog Santa-maria, a transmembrane receptor, which is specifically expressed in embryonic phagocytic glia and plays a major role in the recognition and engulfment steps of phagocytosis. The data demonstrate that santa-maria genetically interacts with simu and draper, while the protein product binds apoptotic cells and physically interacts with the SIMU protein. Moreover, triple knockout of genes for all three glial phagocytic receptors (i.e., simu, draper, and santa-maria) causes partial lethality, thus illuminating their role in development, particularly in the developing nervous system. | Zhang, S., Luo, X., Yuan, X., Wu, D., Liu, J., Zhao, K., Xu, Y., Zhou, J., Li, X., Li, Q. X. (2025).Crystal Structure of Autophagy-Associated Protein 8 at 1.36 A Resolution and Its Inhibitory Interactions with Indole Analogs. J Agric Food Chem, 73(12):7111-7120 PubMed ID: 40066832
Summary: Autophagy-associated protein 8 successfully resolved the crystal structure of Drosophila melanogaster ATG8a (DmATG8a) at 1.36 Å resolution. Being distinct from previously characterized ATG8 homologues, DmATG8a (121 residues) adopts a unique fold comprising five α-helices and four β-folding strands, in contrast to the canonical four α-helices and four β-folding strands observed in other ATG8 proteins. DmATG8a features two active cavities: hydrophobic pocket 1 (HP1) and hydrophobic pocket 2 (HP2), which are essential for the normal physiological function of ATG8. Indole and its analogs can bind specifically with HP1. Microscale thermophoresis results demonstrated a strong affinity of 6-fluoroindole with DmATG8a (3.54 μmol/L), but no affinity with the DmATG8a(K48A) mutant, suggesting that Lys48 is critical in binding 6-fluoroindole probably via a hydrogen bond interaction. The half-maximum lethal concentration (LC(50)) of 6-fluoroindole against D. melanogaster adult flies was 169 μg/mL. These findings establish DmATG8a as a promising target for developing indole-based insecticides. |
Wednesday, June 24th - Genes, RNAs and Proteins |
| de Lange, M., Yarosh, V., Farell, K., McDonnell, C., Patil, R., Hawthorn, I., Jung, M. M., Wenje, S., Steinert, J. R. (2025). High fat diet induces differential age- and gender-dependent changes in neuronal function in Drosophila linked to redox stress. Behav Brain Res, 484:115510 PubMed ID: 40010512
Summary: The prevalence of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, is steadily increasing, thus posing significant challenges to global healthcare systems. Emerging evidence suggests that dietary habits, particularly consumption of high-fat diets, may play a pivotal role in the development and progression of neurodegenerative disorders. Moreover, several studies have shed light on the intricate communication between the gut and the brain, linking gut health with neuroinflammation and its involvement in neurodegenerative processes. This study aims to assess the effects of a high-fat dietary intake on various aspects of neuronal function during aging in a gender specific manner to help understand the potential contributions of diet to neuronal function. To investigate the effects of a high-fat diet, Drosophila melanogaster was used and exposed to a standard normal food diet (NF) and a high-fat diet (HF). Adults were grouped at 10 and 45 days of age in male and female flies reared under the same conditions starting the HF diet at 5 days of age with data showing differential gender- and HF diet-induced phenotypes. Malondialdehyde (MDA) levels were higher in males at 10 and 45 days, caspase-3 expression increased at 45 days implicating apoptosis induction and a reduced climbing activity at 10 and 45 days was apparent in females only. Adult lifespan under both dietary conditions was unchanged when reared at 18° C but odour-associated learning ability was reduced in larvae reared in a HF diet throughout their development. This is the first study to characterise effects of a HF diet on neuronal phenotypes in an age- and gender-specific manner in a Drosophila model. These findings suggest a HF diet induces differential effects of neuronal dysfunction with age and sex-specific outcomes, characterised by enhanced oxidative stress and cell death impacting on behaviour. | Eller, L., Wang, L., Gok, M. O., Hocaoglu, H., Qin, S., Gupta, P., Sieber, M. H. (2025). GSK3 coordinately regulates mitochondrial activity and nucleotide metabolism in quiescent oocytes. Biol Open, 14(3) PubMed ID: 40067254
Summary: As cells transition between periods of growth and quiescence, their metabolic demands change. During this transition, cells must coordinate changes in mitochondrial function with the induction of biosynthetic processes. Mitochondrial metabolism and nucleotide biosynthesis are key rate-limiting factors in regulating early growth. However, it remains unclear what coordinates these mechanisms in developmental systems. This study shows that during quiescence, as mitochondrial activity drops, nucleotide breakdown increases. However, at fertilization, mitochondrial oxidative metabolism and nucleotide biosynthesis are coordinately activated to support early embryogenesis. This study found that the serine/threonine kinase GSK3 is a key factor in coordinating mitochondrial metabolism with nucleotide biosynthesis during transitions between quiescence and growth. Silencing GSK3 in quiescent oocytes causes increased levels of mitochondrial activity and a shift in the levels of several redox metabolites. Interestingly, silencing GSK3 in quiescent oocytes also leads to a precocious induction of nucleotide biosynthesis in quiescent oocytes. Taken together, these data indicate that GSK3 functions to suppress mitochondrial oxidative metabolism and prevent the premature onset of nucleotide biosynthesis in quiescent eggs. These data reveal a key mechanism that coordinates mitochondrial function and nucleotide synthesis with fertilization. |
| Darby, A. M., Keith, S. A., Kalukin, A. A., Lazzaro, B. P. (2025). Chronic bacterial infections exert metabolic costs in Drosophila melanogaster. The Journal of experimental biology, 228(1) PubMed ID: 39801480
Summary: Bacterial infections can substantially impact host metabolic health as a result of the direct and indirect demands of sustaining an immune response and of nutrient piracy by the pathogen itself. Drosophila melanogaster and other insects that survive a sublethal bacterial infection often carry substantial pathogen burdens for the remainder of life. This study asked whether these chronic infections exact metabolic costs for the host, and how these costs scale with the severity of chronic infection. D. melanogaster was infected with four bacterial species (Providencia rettgeri, Serratia marcescens, Enterococcus faecalis and Lactococcus lactis), and metabolic traits were assayed in chronically infected survivors. D. melanogaster carrying chronic infections were uniformly more susceptible to starvation than uninfected controls, and that sensitivity to starvation escalated with higher chronic pathogen burden. Some evidence was observed for greater depletion of triglyceride and glycogen stores in D. melanogaster carrying chronic bacterial loads, although this varied among bacterial species. Chronically infected flies exhibit sustained upregulation of the immune response, which is hypothesized might contribute to the metabolic costs. Consistent with this prediction, genetic activation of the major innate immune signaling pathways depleted metabolic stores and increased starvation sensitivity even in the absence of infection. These results demonstrate that even sublethal infections can have substantial health and fitness consequences for the hosts, arising in part from pathogen-induced immune activation, and that the consequences scale quantitatively with the severity of infection. | Chung, O. W., Yao, S., Yang, F., Wang, L., Cerda-Smith, C., Hutchinson, H. M., Wood, K. C., Su, W., Khasraw, M., Zou, L., Ramsden, D. A., Zhang, Z. Z. (2025). BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance. bioRxiv, PubMed ID: 40027615
Summary: Extrachromosomal circular DNA (ecDNA) are commonly produced within the nucleus to drive genome dynamics and heterogeneity, enabling cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here using genome-wide CRISPR screening in human cells, this study identified the BRCA1-A and the LIG4 complexes mediate ecDNA production. Following DNA fragmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively catalyzes ecDNA production in Drosophila and mammals, with patient tumor ecDNA harboring junctions marked by LIG4 activity. Notably, disrupting LIG4 or BRCA1-A in cancer cells impairs ecDNA-mediated adaptation, hindering resistance to both chemotherapy and targeted therapies. Together, this study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers new therapeutic targets to block ecDNA-mediated adaptation for cancer treatment. |
| Avila, A., Lewandowski, A. S., Li, Y., Gui, J., Lee, K. A., Yang, Z., Kim, M., Lyles, J. T., Man, K., Sehgal, A., Chandler, J. D., Zhang, S. L. (2025). A carnitine transporter at the blood-brain barrier modulates sleep via glial lipid metabolism in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 122(4):e2421178122 PubMed ID: 39847335
Summary: To regulate brain function, peripheral compounds must traverse the blood-brain barrier (BBB), an interface between the brain and the circulatory system. To determine whether specific transport mechanisms are relevant for sleep, a BBB-specific inducible RNAi knockdown (iKD) screen was conductedfor genes affecting sleep in Drosophila. Reduced sleep was observed with knockdown of solute carrier CG6126, a carnitine transporter, as determined by isotope flux. These findings suggest that CG6126 regulation of sleep is through the role of the carnitine shuttle in regulating fatty acid metabolism as lipid droplets accumulate in the brains of CG6126 BBB iKD flies. Knocking down mitochondrial carnitine transferases in non-BBB glial cells mimicked the reduced sleep of the CG6126 BBB iKD flies, while bypassing the necessity of carnitine transport with dietary medium-chain fatty acids or palmitoylcarnitine rescued sleep. It is proposed that carnitine transport via CG6126 promotes brain fatty acid metabolism necessary for maintaining sleep. | Heidarian, Y., Fasteen, T. D., Mungcal, L., Buddika, K., Mahmoudzadeh, N. H., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). Hypoxia-inducible factor 1alpha is required to establish the larval glycolytic program in Drosophila melanogaster. bioRxiv, PubMed ID: 39829828
Summary: The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. This study discovered that Sima, the Drosophila ortholog of Hif1α, is also essential for establishing the larval glycolytic program. Using a multi-omics approach, sima mutants fail to properly activate aerobic glycolysis and die during larval development with metabolic defects that phenocopy dERR mutants. Moreover, dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. Considering that the mammalian homologs of ERR and Hif1α also cooperatively regulate aerobic glycolysis in cancer cells, these findings establish the fly as a powerful genetic model for studying the interaction between these two key metabolic regulators. |
Friday, June 19th - RNAs and Transposons |
| Alizada, A., Hannon, G. J., Nicholson, B. C. (2025). Transcriptional regulation of the piRNA pathway by Ovo in animal ovarian germ cells. 39(3-4):221-241 PubMed ID: 39797761
Summary: The gene-regulatory mechanisms controlling the expression of the germline PIWI-interacting RNA (piRNA) pathway components within the gonads of metazoan species remain largely unexplored. In contrast to the male germline piRNA pathway, which in mice is known to be activated by the testis-specific transcription factor A-MYB, the nature of the ovary-specific gene-regulatory network driving the female germline piRNA pathway remains a mystery. Here, using Drosophila as a model, this study combined multiple genomics approaches to reveal the transcription factor Ovo as regulator of the germline piRNA pathway in ovarian germ cells. Ectopic expression of Ovo in ovarian somatic cells activates germline piRNA pathway components, including the ping-pong factors Aubergine, Argonaute-3, and Vasa, leading to assembly of perinuclear cellular structures resembling nuage bodies of germ cells. In ovarian somatic cells, transcription of ovo is repressed by l(3)mbt, thus preventing expression of germline piRNA pathway genes in the soma. Cross-species ChIP-seq and motif analyses demonstrate that Ovo is binding to genomic CCGTTA motifs within the promoters of germline piRNA pathway genes, suggesting a regulation by Ovo in ovaries analogous to that of mammalian A-MYB in testes. These results also show consistent engagement of the Ovo transcription factor family at ovarian piRNA clusters across metazoan species, reflecting a deep evolutionary conservation of this regulatory paradigm from insects to humans. | Wierzbicki, F., Pianezza, R., Selvaraju, D., Eller, M. M., Kofler, R. (2025). On the origin of the P-element invasion in Drosophila simulans. Mob DNA, 16(1):7 PubMed ID: 40011995
Summary: The horizontal transfer (HT) of the P-element is one of the best documented cases of the HT of a transposable element. The P-element invaded natural D. melanogaster populations between 1950 and 1980 following its HT from Drosophila willistoni, a species endemic to South and Central America. Subsequently, it spread in D. simulans populations between 2006 and 2014, following a HT from D. melanogaster. The geographic region where the spread into D. simulans occurred is unclear, as both involved species are cosmopolitan. The P-element differs between these two species by a single base substitution at site 2040, where D. melanogaster carries a 'G' and D. simulans carries an 'A'. It has been hypothesized that this base substitution was a necessary adaptation that enabled the spread of the P-element in D. simulans, potentially explaining the 30-50-year lag between the invasions of D. melanogaster and D. simulans. To test this hypothesis, the invasion dynamics of P-elements were monitored with both alleles in experimental populations of D. melanogaster and D. simulans. The results indicate that the allele at site 2040 has a minimal impact on the invasion dynamics of the P-element and, therefore, was not necessary for the invasion of D. simulans. However, the host species were found to significantly influenced the invasion dynamics, with higher P-element copy numbers accumulating in D. melanogaster than in D. simulans. Finally, based on SNPs segregating in natural D. melanogaster populations, it is suggested that the horizontal transfer of the P-element from D. melanogaster to D. simulans likely occurred around Tasmania. |
| Stanek, T. J., Kneebone, A., Lawlor, M. A., Cao, W., Ellison, C. E. (2025). Complex determinants of R-loop formation at transposable elements and major DNA satellites. Genetics, 229(4) PubMed ID: 40036798
Summary: Aberrant activation of transposable elements (TEs) has been a well-documented source of genomic instability and disease, stemming from their insertion into genes and their imposition of epigenetic effects on nearby loci. However, the extent to which their disruptive effects involve concomitant or subsequent formation of DNA:RNA hybrids (R-loops) remains unknown. This study used DNA:RNA immunoprecipitation followed by high-throughput sequencing (DRIP-seq) to map the R-loop profiles of TEs and satellites in Drosophila melanogaster ovaries in control and rhino knockout flies, where dozens of TE families are derepressed. R-loops were observed to form primarily in LTR retrotransposons that carry A/T-rich sequence motifs, which are known to favor R-loop formation at genes in Drosophila and other species. Evidence is reported of R-loop formation at 11 of 14 highly abundant D. melanogaster DNA satellites. R-loop formation is positively correlated with expression level for both TEs and satellites; however, neither sequence content nor expression fully explain which repeat families form R-loops, suggesting other factors are at play. Finally, by analyzing population frequencies of R-loop-forming TEs, evidence is presented that TE copies with high R-loop signal may be under stronger negative selection, which suggests that R-loop formation by TEs may be deleterious to their host. Collectively, these results provide insight into the determinants of R-loop formation at repetitive elements. | Raak, S. B., Hanley, J. G., O'Donnell, C. (2025). Competition effects regulating the composition of the microRNA pool. J R Soc Interface, 22(223):20240870 PubMed ID: 39965642
Summary: MicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate protein synthesis. During their maturation, multiple types of pre-miRNAs compete for a shared pool of the enzyme Dicer. It is unknown how this competition for a shared resource influences the relative expression of mature miRNAs. This process was studied in a computational model of pre-miRNA maturation, fitted to in vitro Drosophila S2 cell data. Those pre-miRNAs that efficiently interact with Dicer were shown to outcompete other pre-miRNAs, when Dicer is scarce. To test these model predictions, previously published ex vivo mouse striatum data were re-analysed with reduced Dicer1 expression. A proxy measure was calculated for pre-miRNA affinity to TRBP (a protein that loads pre-miRNAs to Dicer). This measures well-predicted mature miRNA levels in the data, validating these assumptions. This was used as a basis to test the the model's predictions through further analysis of the data. Pre-miRNAs were found with strong TRBP association are over-represented in competition conditions, consistent with the modelling. Finally using further simulations, it was discovered that pre-miRNAs with low maturation rates can affect the mature miRNA pool via competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs. |
| Pizzey, A., Sutcliffe, C., Love, J. C., Akabuogu, E., Rattray, M., Ashe, M. P., Ashe, H. L. (2025). Exploiting the SunTag system to study the developmental regulation of mRNA translation. J Cell Sci, 138(6) PubMed ID: 39989130
Summary: The ability to quantitatively study mRNA translation using SunTag imaging is transforming understanding of the translation process. This study expanded the SunTag method to study new aspects of translation regulation in Drosophila. Repression of the maternal hunchback mRNA in the posterior of the Drosophila embryo is a textbook example of translational control. Using SunTag imaging to quantify translation of maternal SunTag-hbhb mRNAs show similar translation efficiency despite having different untranslated regions (UTRs). The SunTag-hb mRNA can be used as a reporter to study ribosome pausing at single-mRNA resolution, by exploiting the conserved xbp1 mRNA and A60 pausing sequences. Finally, the detector component of the SunTag system was adapted to visualise and quantify translation of the short gastrulation (sog) mRNA, encoding an essential secreted extracellular BMP regulator, at the endoplasmic reticulum in fixed and live embryos. Together, these tools will facilitate the future dissection of translation regulatory mechanisms during development. | Selmi, I., Texier, M., Aguirrenbegoa, M., Merce, C., Fraisse-Lepourry, L., Mugat, B., Mohamed, M., Chambeyron, S., Cribbs, D., Di Stefano, L. (2025). The histone demethylase dLsd1 regulates organ size by silencing transposable elements. Commun Biol, 8(1):272 PubMed ID: 39979483
Summary: The specific role of chromatin modifying factors in the timely execution of transcriptional changes in gene expression to regulate organ size remains largely unknown. This study reports that in Drosophila melanogaster depletion of the histone demethylase dLsd1 results in the reduction of wing size. dLsd1 depletion affects cell proliferation and causes an increase in DNA damage and cell death. Mechanistically, Transposable Elements (TEs) were identified as critical dLsd1 targets for organ size determination. Upon dLsd1 loss many TE families are upregulated, and new TE insertions appear. By blocking this new TE activity, it was possible to rescue the wing size phenotype. Collectively, these results reveal that the histone demethylase dLsd1 and maintenance of TE homeostasis are required to ensure proper wing size. |
Tuesday, June 16th - Disease Models |
| Borjon, L. J., de Assis Ferreira, L. C., Trinidad, J. C., Sasic, S., Hohmann, A. G., Tracey, W. D. (2025). Multiple mechanisms of action for an extremely painful venom. Current biology : CB, 35(2):444-453.e444 PubMed ID: 39765227
Summary: Evolutionary arms races can lead to extremely specific and effective defense mechanisms, including venoms that deter predators by targeting nociceptive (pain-sensing) pathways. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. It has been described as "Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand." The effectiveness of the velvet ant sting against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which this study sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals. They share features with vertebrate nociceptors, including conserved sensory receptor channels. Velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels, through a single venom peptide, Do6a. Drosophila Pickpocket is homologous to mammalian acid-sensing ion channels (ASICs). However, Do6a did not produce behavioral signs of nociception in mice, which was instead triggered by other venom peptides that are non-specific and less potent on Drosophila nociceptors. This suggests that Do6a has an insect-specific function. In fact, it was further demonstrated that the velvet ant's sting produced aversive behavior in a predatory praying mantis. Together, these results indicate that velvet ant venom acts through different molecular mechanisms in vertebrates and invertebrates. | Bell, K. M., Brown, A. T., Van Houten, S. K., Blice-Baum, A. C., Kronert, W. A., Loya, A. K., Camillo, J. R. T., Cammarato, A., Corr, D. T., Bernstein, S. I., Swank, D. M. (2025). A Drosophila cardiac myosin increases jump muscle stretch activation and shortening deactivation. Biophysical journal, 124(4):651-666 PubMed ID: 39799399
Summary: Stretch activation (SA), a delayed increase in force production after rapid muscle lengthening, is critical to the function of vertebrate cardiac muscle and insect asynchronous indirect flight muscle. SA enables or increases power generation in muscle types used in a cyclical manner. Recently, myosin isoform expression has been implicated as a mechanism for varying the amplitude of SA in some muscle types. For instance, expressing a larval Drosophila myosin isoform in a muscle type with minimal SA, the Drosophila jump muscle, substantially increased SA amplitude and enabled positive cyclical power generation. To test whether other myosin isoforms could increase SA amplitude and whether the Drosophila heart benefits from SA, two Drosophila cardiac myosin isoforms, CardM1 and CardM2, were identified and they were expressed in Drosophila jump muscle. CardM1, CardM2; control jump muscle fibers all displayed the characteristic phase 3 of SA, with CardM2 SA amplitude ∼60% greater than that of CardM1 and control fibers. Increasing [P(i)] from 0 to 16 mM increased CardM2 SA tension amplitude by 74%, yet had minimal or no effect on CardM1 or control muscle SA amplitude. CardM2 displayed the most prominent phase 3 dip when shortening deactivation was induced, a delayed decrease in force after muscle shortening. The magnitude of CardM2 shortening deactivation tension was ~50% greater than control or CardM1 fibers. This, along with its greater stretch-activated tension, caused CardM2 to be the only isoform to produce positive power when its fiber length was sinusoidally oscillated. The results support the hypotheses that some myosin isoforms enable greater SA tension levels and suggest that the Drosophila heart is benefiting from SA and shortening deactivation in a manner similar to vertebrate hearts. |
| Akpoghiran, O., Strich, A. K., Koh, K. (2024). Effects of sex, mating status, and genetic background on circadian behavior in Drosophila. Front Neurosci, 18:1532868 PubMed ID: 39844849
Summary: Circadian rhythms play a crucial role in regulating behavior, physiology, and health. Sexual dimorphism, a widespread phenomenon across species, influences circadian behaviors. Additionally, post-mating physiological changes in females are known to modulate various behaviors, yet their effects on circadian rhythms remain underexplored. Using Drosophila melanogaster, a powerful model for studying circadian mechanisms, this study systematically assessed the impact of sex and mating status on circadian behavior. Circadian period length and rhythm strength were measured in virgin and mated males and females, including females mated to males lacking Sex Peptide (SP), a key mediator of post-mating changes. Across four wild-type and control strains, this study found that males consistently exhibited shorter circadian periods than females, regardless of mating status, suggesting that circadian period length is a robust sexually dimorphic trait. In contrast, rhythm strength was influenced by the interaction between sex and mating status, with female mating generally reducing rhythm strength in the presence of SP signaling. Notably, genetic background significantly modulated these effects on rhythm strength. These findings demonstrate that while circadian period length is a stable sex-specific trait, rhythm strength is shaped by a complex interplay between sex, mating status, and genetic background. This study advances understanding of how sex and mating influence circadian rhythms in Drosophila and provides a foundation for future research into sexually dimorphic mechanisms underlying human diseases associated with circadian disruptions. | Buchsbaum, E., Schnell, B. (2025). Activity of a descending neuron associated with visually elicited flight saccades in Drosophila. Current biology : CB, 35(3):665-671.e664 PubMed ID: 39788121
Summary: Approaching threats are perceived through visual looming, a rapid expansion of an image on the retina. Visual looming triggers defensive responses such as freezing, flight, turning, or take-off in a wide variety of organisms, from mice to fish to insects. In response to looming, flies perform rapid evasive turns known as saccades. Saccades can also be initiated spontaneously to change direction during flight. Two types of descending neurons (DNs), DNaX (for information on DNaX neurons, go to Google and enter DNaX neurons Drosophila) and DNb01, were previously shown to exhibit activity correlated with both spontaneous and looming-elicited saccades in Drosophila. As they do not receive direct input from the visual system, it has remained unclear how visually elicited flight turns are controlled by the nervous system. DNp03 receives input from looming-sensitive visual projection neurons and provides output to wing motor neurons and is therefore a promising candidate for controlling flight saccades. Using whole-cell patch-clamp recordings from DNp03 in head-fixed flying Drosophila, DNp03 was shown to respond to ipsilateral visual looming in a behavioral-state-dependent manner. How DNp03 activity relates to the variable behavioral output was explored. Sustained DNp03 activity, persisting after the visual stimulus, was the strongest predictor of saccade execution. However, DNp03 activity alone cannot fully explain the variability in behavioral responses. Combined with optogenetic activation experiments during free flight, these results suggest an important but not exclusive role for DNp03 in controlling saccades, advancing understanding of how visual information is transformed into motor commands for rapid evasive maneuvers in flying insects. ] |
| Sabandal, P. R., Kim, Y. C., Sabandal, J. M., Han, K. A. (2025). Social context and dopamine signaling converge in the mushroom body to drive impulsivity. bioRxiv, PubMed ID: 40027633
Summary: Organisms adapt their behaviors flexibly in response to various internal and environmental factors. However, how and where these factors converge in the brain to alter behavior is not well understood. This study examined how social context interacts with dopamine activity to influence inhibitory control in Drosophila. Regardless of social context-whether isolated or in groups-wild-type flies consistently showed strong movement suppression in a go/no-go task that measures action restraint. In contrast, flies with enhanced dopamine activity suppressed their movements when tested alone or with potential mates but exhibited impulsive behaviors when exposed to same-sex peers. This social-context-dependent impulsivity was shown to rely on dopamine-D1 receptor-cAMP signaling in mushroom body (MB) neurons. Remarkably, activating the MB was sufficient to induce impulsivity, even without dopamine input or a social context. These findings highlight MB as a critical hub where social context and dopamine signaling converge to regulate impulsive behavior in Drosophila. | Sato, D. X., Okuyama, T., Takahashi, Y. (2025). Multifaceted and extensive behavioral trajectories of genomically diverse Drosophila lines. Sci Data, 12(1):400 PubMed ID: 40055352
Summary: Detailed tracking data is essential to understanding the intricate mechanisms behind animal behavior. This study presents a comprehensive dataset containing behavioral movies and trajectories from over 30,000 Drosophila melanogaster individuals across 105 genetically distinct strains, including 104 wild-type strains from the Drosophila Genetic Reference Panel, along with one visually impaired mutant. These data, categorized by genetic background, sex, and social context (isolated or in groups), were collected during 15-minute sessions that included five minutes of repeated looming stimuli to elicit fear responses. Additionally, the experimental design incorporated group experiments with randomly combined pairs of strains to investigate synergistic effects of group members on behavioral dynamics. Beyond enabling detailed analyses of genetic factors underlying locomotion, fear responses, and social interactions, this dataset provides a unique opportunity to examine individual behavioral variability within genetically identical flies. By capturing a broad spectrum of behaviors across different genetic and environmental contexts, these data serve as a valuable resource for advancing understanding of how genetics, individuality, and group interactions shape animal behavior. |
Tuesday, June 9th - Disease Models |
| Hanson, K. M., Macdonald, S. J. (2024). Dynamic Changes in Gene Expression Through Aging in Drosophila melanogaster Heads. bioRxiv, PubMed ID: 39764034
Summary: Work in many systems has shown large-scale changes in gene expression during aging. However, many studies employ just two, arbitrarily-chosen timepoints at which to measure expression, and can only observe an increase or a decrease in expression between "young" and "old" animals, failing to capture any dynamic, non-linear changes that occur throughout the aging process. This study used RNA sequencing to measure expression in male head tissue at 15 timepoints through the lifespan of an inbred Drosophila melanogaster strain. >6,000 significant, age-related genes were detected, nearly all of which have been seen in previous fly aging expression studies, and which include several known to harbor lifespan-altering mutations. The gene set was grouped into 28 clusters via their temporal expression change, observing a diversity of trajectories; some clusters show a linear change over time, while others show more complex, non-linear patterns. Notably, re-analysis of the dataset comparing the earliest and latest timepoints - mimicking a two-timepoint design - revealed fewer differentially-expressed genes (around 4,500). Additionally, those genes exhibiting complex expression trajectories in the multi-timepoint analysis were most impacted in this re-analysis; Their identification, and the inferred change in gene expression with age, was often dependent on the timepoints chosen. Informed by the trajectory-based clusters, a series of gene enrichment analyses were executed, identifying enriched functions/pathways in all clusters, including the commonly seen increase in stress- and immune-related gene expression with age. Finally, a pair of accessible shiny apps were developed to enable exploration of the differential expression and gene enrichment results. | Beamish, C. R., Becker, J., Tam, L. M., Love, T., Rand, M. D. (2025). Transcriptomic analysis identifies muscle-specific mitochondrial and vesicular transport genes as methylmercury toxicity targets in a Drosophila model of congenital Minamata disease. Toxicol Sci, 205(1):106-123 PubMed ID: 39951334
Summary: Prenatal methylmercury (MeHg) exposure presents a heightened concern in early human development, as has been exemplified in historic cases of congenital minimata disease (CMD). Children who experience CMD characteristically present with various degrees of cognitive and motor symptoms and signs, much like cerebral palsy. MeHg has thus been characterized as a neurotoxicant, where motor deficits are ascribed to central nervous system targets. Skeletal muscle as a post-synaptic MeHg target and contributor to the etiology of CMD has garnered far less attention. Prior studies using Drosophila to model CMD revealed that developmental exposure of MeHg in the larval/pupal stages can elicit graded and latent dose responses affecting adult flight behavior at lower doses (0.4-2.5 ppm in food) and eclosion (emergence from the pupa case) at higher doses (>2.5 ppm in food). The latter phenotype is accompanied by dysmorphogenesis of skeletal muscles. This study investigated respective roles for muscle and neural targets in MeHg toxicity. Using RNA-seq analysis, developmental MeHg exposure was found to produce 10 times as many differentially expressed transcripts in indirect flight muscle compared to the ventral nerve cord. Among known MeHg response genes, Nrf2 antioxidant response pathway genes showed muscle-specific MeHg-induced expression changes. Within the muscle transcriptome, the most enriched and significant Gene Ontology terms identified genes required for mitochondrial ribosomal translation at the pupa stage and mitochondrial function (respiratory chain complex I) and vesicle trafficking (ESCRT III) pathways in adults, all showing decreased expression with MeHg exposure. By using an intact, whole-animal developmental model, this study identified preferential candidates to evaluate a novel role for muscle-specific mitochondria and intercellular vesicular communication mechanisms as targets in MeHg toxicity and the etiology of CMD. |
| Chaudhary, S., Iyer, S. M., Tare, M. (2025). Wild-Type Drosophila melanogaster Strains Respond Differentially to Rotenone Exposure]. MicroPubl Biol, 2025 PubMed ID: 39936041
Summary: Drosophila melanogaster has been established as a reliable in vivo model for studying human diseases. However, the varied designs of such studies and the different origins of the strains have significantly contributed to metabolic and molecular differences between strains. Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons, leading to various motor and non-motor symptoms including but not limited to bradykinesia, postural instability, cognitive decline, and gut dysbiosis. Chronic exposure to toxins such as rotenone can induce neuronal cell death. This study has developed a sporadic PD model by direct feeding of rotenone-supplemented food to Drosophila melanogaster wild-type strains, which has previously been shown to cause neuronal cell death and used to mimic PD in Drosophila. Upon exposure to rotenone in two wild-type strains (Oregon-R and Canton-S) , differences in their climbing ability and lifespan were monitored. The degree of motor defects upon rotenone exposure is higher in Oregon-R compared to age-matched Canton-S flies. It was also observed that the Canton-S flies (rotenone-fed and non-rotenone-fed) exhibited a lower survival percentage than Oregon-R flies. However, the climbing defects in Canton-S flies are not as pronounced as in Oregon-R flies. The mechanism(s) involved in such differential effects in different wild-type Drosophila strains are yet to be explored and may provide a perspective on differential symptoms of PD patients belonging to different demographics. | Zhu, K., Ni, H., Hafeez, E., Hu, Y., Hu, F., Du, D., Chen, D. (2025). Effects of Silibinin on Delaying Aging in Drosophila melanogaster. Antioxidants (Basel), 14(2) PubMed ID: 40002334
Summary: Aging is an inevitable physiological process, but delaying aging has always been an enduring human pursuit. Silibinin (SIL), derived from the seeds of the milk thistle plant, exhibits a broad spectrum of pharmacological properties, including anti-tumor effects, liver protection, inhibition of apoptosis, and alleviation of inflammation. However, whether it has anti-aging effects remains unclear. The SIL dietary supplement to Drosophila melanogaster prolonged lifespan, improved climbing ability, ameliorated age-associated intestinal barrier disruption, enhanced the resistance to oxidative stress, and increased the enzyme activities of superoxide dismutase (SOD) and catalase (CAT). Furthermore, RNA-seq results showed that SIL addition significantly upregulated 74 genes and downregulated 50 genes compared with the control. KEGG (Kyoto Encyclopedia of genes and genomes) analysis demonstrated that these differentially expressed genes were primarily involved in the Toll signaling pathway and endoplasmic reticulum proteins processing, six among which, including IM2, IM3, Drsl3, CG7556, GCS1, and TRAM, were particularly involved in the regulation by SIL supplementation. The results indicate that SIL exhibits anti-aging effects by enhancing antioxidant capacity and regulating aging-related signaling pathways. Therefore, SIL shows a potential application in anti-aging dietary regimens. |
| Yadav, A., Ouyang, X., Barkley, M., Watson, J. C., Madamanchi, K., Kramer, J., Zhang, J., Melkani, G. (2025). Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2. JbioRxiv, PubMed ID: 40027815
Summary: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. While mutations in the Amyloid Precursor Protein (APP) and Aβ42 accumulation contribute to AD, the mechanisms linking Aβ to lipid metabolism and neuroinflammation remain unclear. Using Drosophila models, this study showed that App (NLG) and Aβ42 expression causes locomotor deficits, disrupted sleep, memory impairments, lipid accumulation, synaptic loss, and neuroinflammation. Similar lipid and inflammatory changes are observed in the App (NLG-F) knock-in mouse model, reinforcing their role in AD pathogenesis. Diacylglycerol O-acyltransferase 2 (Dgat2), a key lipid metabolism enzyme, as a modulator of AD phenotypes. In Drosophila and mouse AD models, Dgat2 levels and its transcription factors are altered. Dgat2 knockdown in Drosophila reduced lipid accumulation, restored synaptic integrity, improved locomotor and cognitive function, and mitigated neuroinflammation. Additionally, Dgat2 modulation improved sleep and circadian rhythms. In App (NLG-F) mice, Dgat2 inhibition decreased neuroinflammation and reduced AD risk gene expression. These findings highlight the intricate link between amyloid pathology, lipid dysregulation, and neuroinflammation, suggesting that targeting Dgat2 may offer a novel therapeutic approach for AD. Conserved lipid homeostasis mechanisms across species provide valuable translational insights. | Leventhal, M. J., Zanella, C. A., Kang, B., Peng, J., Gritsch, D., Liao, Z., Bukhari, H., Wang, T., Pao, P. C., Danquah, S., Benetatos, J., Nehme, R., Farhi, S., Tsai, L. H., Dong, X., Scherzer, C. R., Feany, M. B., Fraenkel, E. (2025). An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration. Nat Commun, 16(1):4441 PubMed ID: 40393985
Summary: Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, an unbiased, genome-scale forward genetic screen was conducted for age-associated neurodegeneration in Drosophila. Proteomics, phosphoproteomics, and metabolomics were measured in Drosophila models of Alzheimer's disease and Alzheimer's genetic variants were identified that modify gene expression in disease-vulnerable neurons in humans. A network model was used to integrate these data with previously published Alzheimer's disease proteomics, lipidomics and genomics. This study computationally predicted and experimentally confirmed how HNRNPA2B1 and MEPCE enhance toxicity of the tau protein, a pathological feature of Alzheimer's disease. Furthermore, the screen hit CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human stem cell-derived neural progenitor cells. This study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease. ] |
| Oh, J., Catherine, C., Kim, E. S., Min, K. W., Jeong, H. C., Kim, H., Kim, M., Ahn, S. H., Lukianenko, N., Jo, M. G., Bak, H. S., Lim, S., Kim, Y. K., Kim, H. M., Lee, S. B., Cho, H. (2025). Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin. Nat Commun, 16(1):737 PubMed ID: 39824813
Summary: Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington's disease (HD). Since no current treatment delays the progression of HD, this study developws a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. The ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, was engineered to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, two yeast PEX19 variants were identified and equivalent mutations were engineered into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, these data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD. | Shao, Y., Hu, J., Yan, K., Zheng, K., Sha, W., Wang, J., Wu, J., Huang, Y. (2025). Impaired mitochondrial integrity and compromised energy production underscore the mechanism underlying CoASY protein-associated neurodegeneration. Cell Mol Life Sci, 82(1):84 PubMed ID: 39985665
Summary: Coenzyme A (CoA) is a crucial metabolite involved in various biological processes, encompassing lipid metabolism, regulation of mitochondrial function, and membrane modeling. CoA deficiency is associated with severe human diseases, such as Pantothenate Kinase-Associated Neurodegeneration (PKAN) and CoASY protein-associated neurodegeneration (CoPAN), which are linked to genetic mutations in Pantothenate Kinase 2 (PANK2) and CoA Synthase (CoASY). Although the association between CoA deficiency and mitochondrial dysfunction has been established, the underlying molecular alterations and mechanisms remain largely elusive. This study investigated the detailed changes resulting from the functional decline of CoASY using the Drosophila model. These findings revealed that a reduction of CoASY in muscle and brain led to degenerative phenotypes and apoptosis, accompanied by impaired mitochondrial integrity. The release of mitochondrial DNA was notably augmented, while the assembly and activity of mitochondrial electron transport chain (ETC) complexes, particularly complex I and III, were diminished. Consequently, this resulted in decreased ATP generation, rendering the fly more susceptible to energy insufficiency. These findings suggest that compromised mitochondrial integrity and energy supply play a crucial role in the pathogenesis associated with CoA deficiency, thereby implying that enhancing mitochondrial integrity can be considered a potential therapeutic strategy in future interventions. |
Thursday, June 4th - Gonads |
| Pozmanter, C., Benner, L., Kelly, S. E., Curnutte, H., Emilfork, L., Van Doren, M. (2025). Tudor domain containing protein 5-like identifies a novel germline body and regulates maternal RNAs during oogenesis in Drosophila. Genetics, 229(4) PubMed ID: 39982762
Summary: Tudor domain-containing proteins are conserved across the animal kingdom for their function in germline development and fertility. Previous work demonstrated that Tudor domain-containing protein 5-like plays an important role in the germline where it promotes male identity. However, Tudor domain-containing protein 5-like is also expressed in both the ovary and testis during later stages of germline development, suggesting that it plays a role in germline differentiation in both sexes. Tudor domain-containing protein 5-like localizes to a potentially novel germline body and plays a role in posttranscriptional gene regulation. Additionally, embryos laid by Tdrd5l-mutant females exhibited reduced viability and displayed dorsal appendage defects suggesting a failure of proper dorsal-ventral patterning. As dorsal-ventral patterning is dependent on gurken (grk), Gurken expression was examined during oogenesis. Premature accumulation of Gurken protein was observed in nurse cells indicating that translation is no longer properly repressed during mRNA transport to the oocyte. Increased nurse cell accumulation of the cytoplasmic polyadenylation element binding protein Oo18 RNA-binding protein, a translational activator of grk. Decreasing orb function was able to partially rescue the Tdrd5l-mutant phenotype, and so defects in Orb expression are likely a primary cause of the defects in Tdrd5l mutants. These data indicate that Tdrd5l is important for translational repression of maternal mRNAs such as orb, and possibly others, following their synthesis in the nurse cells and during their transport to the oocyte. | Messer, C. L., Burghardt, E., McDonald, J. A. (2025). A deficiency screen of the X chromosome for Rap1 GTPase dominant interacting genes in Drosophila border cell migration. G3 (Bethesda), 15(5) PubMed ID: 39993182
Summary: Collective cell migration is critical to embryonic development, wound healing, and the immune response, but also drives tumor dissemination. Understanding how cell collectives coordinate migration in vivo has been a challenge, with potential therapeutic benefits that range from addressing developmental defects to designing targeted cancer treatments. The small GTPase Rap1 has emerged as a regulator of both embryogenesis and cancer cell migration. How active Rap1 coordinates downstream signaling functions required for coordinated collective migration is poorly understood. Drosophila border cells undergo a stereotyped and genetically tractable in vivo migration within the developing egg chamber of the ovary. This group of 6-8 cells migrates through a densely packed tissue microenvironment and serves as an excellent model for collective cell migration during development and disease. Rap1, like all small GTPases, has distinct activity state switches that link extracellular signals to organized cell behaviors. Proper regulation of Rap1 activity is essential for successful border cell migration yet the signaling partners and other downstream effectors are poorly characterized. Using the known requirement for Rap1 in border cell migration, a dominant suppressor screen was conducted for genes whose heterozygous loss modifies the migration defects observed upon constitutively active Rap1V12 expression. This study identified 7 genomic regions on the X chromosome that interact with Rap1V12. Three genomic regions were mapped to single Rap1-interacting genes, frizzled 4, Ubiquitin-specific protease 16/45, and strawberry notch. Thus, this unbiased screening approach identified multiple new candidate regulators of Rap1 activity with roles in collective border cell migration. |
| Kolotuev, I., Williams, A., Kizilyaprak, C., Pellegrino, S., Lewellyn, L. (2025). Complementary Volume Electron Microscopy-based approaches reveal ultrastructural changes in germline intercellular bridges of D. melanogaster. bioRxiv, PubMed ID: 40027623
Summary: Intercellular bridges are essential to connect developing germline cells. The Drosophila melanogaster egg chamber is a powerful model system to study germline intercellular bridges, or ring canals (RCs). RCs connect the developing oocyte to supporting nurse cells, and defects in their stability or growth lead to infertility. Despite their importance, it has been technically difficult to use electron microscopy-based approaches to monitor changes in RC structure during oogenesis. This study describes the application of a complementary set of volume EM-based approaches to visualize ultrastructural changes in the germline RCs. The combination of array tomography (AT) and focused ion beam (FIB) scanning electron microscopy (SEM) has allowed gaining of insight into previously unappreciated aspects of RC structure. It was possible to quantify differences in RC size and thickness within and between germ cell clusters at different developmental stages. Within a cluster, RC size correlates with lineage; the largest RCs were formed during the first division, and the smallest RCs were formed during the fourth mitotic division. The formation of membrane interdigitations was observed in the vicinity of RCs much earlier than previously reported, and reconstruction of a RC from a mid-stage EC provided insight into the 3D orientation of these extensive cell-cell contacts. Imaging also revealed a novel membrane structure that appeared to line the interior of the RC lumen. Although the focus was on ultrastructural changes in the germline RCs, the dataset contains valuable details of additional cell types and structures, including the fusome, the germline stem cells and their niche, and the migrating border cells. This imaging framework could be applied to other tissues or samples that face similar technical challenges, where the small structure of interest is located within a large sample volume. | Kilwein, M. D., Miller, P., Lee, K. Y., Osterfield, M., Mogilner, A., Shvartsman, S. Y., Gavis, E. R. (2025). Formation of Drosophila germ cells requires spatial patterning of phospholipids. Curr Biol, 35(7):1612-1621. PubMed ID: 40049172
Summary: Germline-soma segregation is crucial for fertility. Primordial germ cells (PGCs) arise early in development and are the very first cells to form in the Drosophila embryo. At the time of PGC formation, the embryo is a syncytium where nuclei divide within a common cytoplasm. Whereas invaginating plasma membrane furrows enclose nuclei to form somatic lineages during the 14th nuclear division cycle, PGCs emerge from the syncytium during the 9th division cycle in a mechanistically distinct process. PGC formation depends on maternally deposited germ granules localized at the embryo's posterior pole. Germ granules trigger protrusion of membrane buds that enlarge to surround several nuclei that reach the posterior pole. Buds are remodeled to cells through mitotic division and constriction of the bud neck. Previous studies implicated F-actin, actin regulators, and contractile ring components in mitotic furrow formation, but what drives bud emergence and how germ granules provoke reshaping of the plasma membrane remain unknown. This study investigated the mechanism of germ-granule-induced bud formation. Treating the embryo as a pressurized elastic shell, mathematical modeling was used to examine possible mechanical mechanisms for local membrane protrusion. One mechanism, outward buckling produced by polymerization of a branched F-actin network, is supported by experimental data. Further, germ granules were shown to modify membrane lipid composition, promoting local branched F-actin polymerization that initiates PGC formation. It is proposed that a mechanism for membrane lipid regulation of F-actin dynamics in migrating cells has been adapted for PGC formation in response to spatial cues provided by germ granules. ] |
| Zike, A. B., Abel, M. G., Fleck, S. A., DeWitt, E. D., Weaver, L. N. (2025). Estrogen-Related Receptor is Required in Adult Drosophila Females for Germline Stem Cell Maintenance. bioRxiv, PubMed ID: 40034644
Summary: Stem cell self-renewal and proper tissue function rely on conserved metabolic regulators to balance energy production with inter-organ metabolic trafficking. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism. In mammals, ERRs have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole Drosophila ERR ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, ERR is required in adult Drosophila males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing of the role of ERR in Drosophila metabolism, whether ERR has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in Drosophila, the established adult female germline stem cell (GSC) lineage was used as a model. Whole-body ERR knockout in adult females using conditional heat shock-driven FLP-FRT recombination significantly reduces egg production and decreases GSC number. In addition, this study found that ERR activity is required cell-autonomously in the adult female germline for maintenance of GSCs; whereas ERR regulation of GSCs is independent of its activity in adult female adipocytes. These results highlight an ancient and conserved role for ERRs in the regulation of stem cell self-renewal. | Samuels, T. J., Torley, E. J., Nadmitova, V., Naden, E. L., Blair, P. E., Hernandez Frometa, F. A., Karam Teixeira, F. (2025). Destabilisation of bam transcripts terminates the mitotic phase of Drosophila female germline differentiation. Development, 152(5) PubMed ID: 39964294
Summary: The tight control of the mitotic phase of differentiation is crucial to prevent tumourigenesis while securing tissue homeostasis. In the Drosophila female germline, differentiation involves precisely four mitotic divisions, and accumulating evidence suggests that bag of marbles (bam), the initiator of differentiation, is also involved in controlling the number of divisions. To test this hypothesis, Bam was depleted from differentiating cells and a reduced number of mitotic divisions was found. The regulation of Bam was found using RNA imaging methods; the bam 3' UTR was found to convey instability to the transcript in the eight-cell cyst and early 16-cell cyst. The RNA-binding protein Rbp9 is responsible for timing bam mRNA decay. Rbp9 itself is part of a sequential cascade of RNA-binding proteins activated downstream of Bam, and was found to be regulated through a change in transcription start site, driven by Rbfox1. Altogether, a model is proposed in which Bam expression at the beginning of differentiation initiates a series of events that eventually terminates the Bam expression domain. |
Tuesday, June 2nd - Evolutionary Homologs |
| Wolff, J. M., Lang, K., Chen, M., Milosavljevic, J., Kayser, S., Helmstadter, M., Walz, G., Abed, A., Gerstner, L., Bahar, S., Ulbrich, M. H., Hermle, T. (2025). Transgenic human nephrin in Drosophila nephrocytes facilitates variant analysis. Kidney Int, 108(1):57-73 PubMed ID: 40316169
Summary: Nephrin, the key structural protein of the slit diaphragm, is encoded by NPHS1. Pathogenic variants in this gene are the primary cause of congenital nephrotic syndrome. About 400 variants have been described but functional characterization in vitro is very limited. This study expressed human nephrin in Drosophila nephrocytes, which possess a molecularly conserved slit diaphragm to facilitate functional studies. Immunofluorescence of the human transgene revealed assembly into a complex linear architecture after silencing of sns, the Drosophila nephrin. This pattern suggests lateral clustering of human nephrin into a macromolecular configuration which resembles nephrin in vivo but is absent in cultured cells. In Drosophila nephrocytes, transgenic nephrin colocalized with the endogenous slit diaphragm proteins Pyd and Kirre, indicating a hybrid multi-protein complex. Transmission electron microscopy with pre-embedding immunogold labeling revealed an atypical, tubular ultrastructure. The linear nephrin did not adequately restore membrane invaginations, endocytic function or cellular survival, suggesting that proper signaling function requires additional indispensable cofactors. Murine NEPH1 alone was insufficient but associated with transgenic nephrin. Notably, the linear nephrin assembly provided a read-out for investigation of patient-derived variants. This distinct pattern was altered in transgenes reflecting patient variants with milder clinical presentation, including novel variant NPHS1-V1241G. The impact on the pattern largely correlated with the age of onset of nephrotic syndrome of the respective variant, as demonstrated by automated image annotation for quantitative evaluation. These findings demonstrate that transgenesis of NPHS1 in nephrocytes is a viable approach for investigation of slit diaphragm formation and precise functional characterization of patient variants. | Tzou, F. Y., Chuang, P. H., Hsu, C. H., Wu, C. H., Hsiao, Y., Liu, C. C., Yu, Y. L., Yeh, Y. H., Lin, C. W., Chan, C. C., Huang, S. Y. (2025). Dihydroceramide desaturase modulates autolysosome maturation and ameliorates CRB1 retinopathy. Biochim Biophys Acta Mol Basis Dis, 1871(5):167736 PubMed ID: 39965731
Summary: Variants in the CRB1 gene cause retinal degeneration and subsequent vision impairment in patients of retinitis pigmentosa (RP). No treatments are currently available to cure or impede the progression of CRB1-associated retinopathy. Previous studies have revealed alterations in the endolysosomal systems and autophagy in the absence of CRB1, but their roles in the pathogenesis of CRB1 retinopathy are unclear. This study examined the disease mechanism of CRB1 retinopathy using loss-of-function mutants of crumbs (crb), the Drosophila homolog of CRB1. The loss of crb results in overactivation of autophagy in the eye. This study also discovered that dihydroceramide desaturase encoded by infertile crescent (ifc), was up-regulated in crb mutants. Overexpression of ifc inhibited autolysosomes and alleviated Atg1-induced autophagic cell death. Mechanistically, ifc enhanced the binding of Rac1 to Atg8 and increased the autophagosomal localization of active Rac1, thus inhibiting autophagy. Importantly, autophagy inhibitions achieved through ifc overexpression, chloroquine treatment, or Beclin-1 RNAi all ameliorated the neurodegeneration of crb mutant eyes. Together, these findings highlight the mechanism of dihydroceramide desaturase in modulating autolysosome functions in crb mutants, providing new insights for developing treatments against CRB1 retinopathy. |
| Deng, W., Carr, R. L., Kaul, R. R., Pavlova-Deb, M., Haage, A., Roca-Cusachs, P., Tanentzapf, G. (2025). Consolidation of cell-ECM adhesion through direct talin-mediated actin linkage is essential for mouse embryonic morphogenesis. Commun Biol, 8(1):948 PubMed ID: 40544224
Summary: During animal development, cell-ECM adhesion mediated by integrins is required for the assembly and maintenance of tissues and organs. It can either be transient or stable and requires linking integrins to the cytoskeleton. Talin can link integrins to actin either directly through its actin-binding sites (ABSs) or indirectly by recruiting downstream actin-binding molecules. In Drosophila, talin's ABS3 domain is essential for biological functions, but its role remains unknown in mammalian systems. This study investigated the role of direct talin-mediated actin linkage in mammals by generating a mouse model containing point mutations in talin's ABS3 domain. Mutant mice exhibit early developmental defects and die midway through embryogenesis. Primary mouse embryonic fibroblasts generated from mutants form prominent focal adhesions but show defective consolidation and maturation. Adhesion dynamics, cell spreading, actin dynamics and organization, and traction force generation are also impacted in mutants, which affect processes such as cell migration that impinge on multiple events during early mouse embryogenesis. Overall, this work provides key mechanistic insights into how direct coupling of ECM to actin through talin has specific and critical roles in controlling adhesion dynamics required for early mammalian development. | Xiong, C., Kandhan, P., Zoltowski, B. D., Tao, P. (2025). Structural Plasticity and Functional Dynamics of Pigeon Cryptochrome 4 as Avian Magnetoreceptor. J Mol Biol:169233 PubMed ID: 40441417
Summary: Cryptochromes (CRYs) are key flavoproteins involved in biological processes such as circadian rhythm regulation and magnetoreception. Type IV CRYs have been identified as primary candidates for avian magnetoreception. However, their structural flexibility, particularly within the cryptochrome C-terminal extension (CCE) and phosphate-binding loop (PBL), remains poorly understood. This study employed temperature replica exchange molecular dynamics (T-REMD) simulations combined with advanced dimensionality reduction techniques, including autoencoder and time-lagged independent component analysis (t-ICA), to explore the conformational space of Columba livia cryptochrome 4 (ClCRY4), as the only available crystal structure of Type IV CRYs to date. By using Drosophila cryptochrome (dCRY) as a reference structure,the reliability of T-REMD sampling in capturing key states of ClCRY4 was assessed. The results indicate that the CCE region of ClCRY4 displays unique conformational dynamics and cooperative interactions with the PBL, highlighting the need for further investigation. The clustering analysis of ClCRY4 conformations revealed multiple structural states, underscoring the functional significance of its intrinsically disordered regions (IDRs). This study provides a novel computational approach for studies of CRYs dynamics, through which the modeling of one CRY with full structure could be used to benchmark the computational study of another CRY only with partial structural information available. |
| v | Angermeier, A., Yu, D., Huang, Y., Marchetto, S., Borg, J. P., Chang, C., Wang, J. (2025). Dact1 induces Dishevelled oligomerization to facilitate binding partner switch and signalosome formation during convergent extension. Nat Commun, 16(1):2425 PubMed ID: 40069199
Summary: Convergent extension (CE) is a universal morphogenetic engine that promotes polarized tissue extension. In vertebrates, CE is regulated by non-canonical Wnt ligands signaling through "core" proteins of the planar cell polarity (PCP) pathway, including the cytoplasmic protein Dishevelled (Dvl), receptor Frizzled (Fz) and tetraspan protein Van gogh-like (Vangl). PCP was discovered in Drosophila to coordinate polarity in the plane of static epithelium, but does not regulate CE in flies. Existing evidence suggests that adopting PCP for CE might be a vertebrate-specific adaptation with incorporation of new regulators. This study used Xenopus to investigate Dact1, a chordate-specific protein. Dact1 induces Dvl to form oligomers that dissociate from Vangl, but stay attached with Fz as signalosome-like clusters and co-aggregate with Fz into protein patches upon non-canonical Wnt induction. Functionally, Dact1 antagonizes Vangl, and synergizes with wild-type Dvl but not its oligomerization-defective mutants. It is proposed that, by promoting Dvl oligomerization, Dact1 couples Dvl binding partner switch with signalosome-like cluster formation to initiate non-canonical Wnt signaling during vertebrate CE. | Zhang, Y., Li, H., Lan, Q., Liu, X., Wu, H., Zhang, J., Zhao, X., Wang, Y. (2024). Sinuous is a Claudin Required for Locust Molt in Locusta migratoria. Genes, 15(7) PubMed ID: 39062629
Summary: The epidermal cells of insects are polarized epithelial cells that play a pivotal role in the insect's molting process. Sinuous, a pivotal structural protein involved in the formation of septate junctions among epithelial cells, is essential for its physiological function. In this study, to determine whether sinuous participates in the regulation of insect molting, the sinuous gene, Lmsinu, was identified in Locusta migratoria, which encodes a protein belonging to the claudin family and shares 62.6% identity with Drosophila's sinuous protein. Lmsinu is expressed in multiple tissues, and its expression level in the integument significantly increases prior to molting. Knockdown of Lmsinu in L. migratoria results in larval mortality during molting. Furthermore, hematoxylin and eosin and chitin staining demonstrate that the downregulation of Lmsinu led to a prolonged degradation process of the old cuticle during the molting process. Electron microscopy analysis further revealed that knockdown of Lmsinu disrupts the formation of septate junctions among epidermal cells, which are a monolayer of polarized epithelial cells, which may hinder the functionality of epidermal cells during the process of molting. In summary, these findings suggest that Lmsinu plays a role in nymph molting by regulating the formation of septate junctions among epidermal cells. |
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