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September 2026 August 2026 July 2026 June 2026 May 2026 April 2026 March 2026 February 2026 January 2026 December 2025 November 2025 October 2025 September 2025 August2025 July 2025 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 December 2023 December 2022 December 2021 December 2020 December 2019 | Aceves-Ewing, N. M., Lanza, D. G., Marcogliese, P. C., ...., Yamamoto, S., Bellen, H. J., Burrage, L. C., Heaney, J. D. (2025). Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling. medRxiv, PubMed ID: 39677486
Summary: Heterozygous pathogenic variants in AXIN2 (see Drosophila Axin) are associated with oligodontia-colorectal cancer syndrome (ODCRCS), a disorder characterized by oligodontia, colorectal cancer, and in some cases, sparse hair and eyebrows. Four individuals were identified with one of two de novo, heterozygous variants (NM_004655.4:c.196G>A, p.(Glu66Lys) and c.199GA, p.(Gly67Arg)) in AXIN2 whos presentations expand the phenotype of AXIN2-related disorders. In addition to ODCRCS features, these individuals have global developmental delay, microcephaly, and limb, ophthalmologic, and renal abnormalities. Structural modeling of these variants suggests that they disrupt AXIN2 binding to tankyrase (see Drosophila Tankyrase), which regulates AXIN2 levels through PARsylation and subsequent proteasomal degradation. To test whether these variants produce a phenotype in vivo, an innovative prime editing N1 screen was used to phenotype heterozygous (p.E66K) mouse embryos, which were perinatal lethal with short palate and skeletal abnormalities, contrary to published viable Axin2 null mouse models. Modeling of the p.E66K variant in the Drosophila wing, using transgenic flies that express AXIN2, revealed gain-of-function activity compared to reference AXIN2. However, the variant showed loss-of-function activity in the fly eye compared to reference AXIN2, suggesting that the mechanism by which p.E66K affects AXIN2 function is cell context-dependent. Together, these studies in humans, mice, and flies demonstrate that specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with context-dependent effects on AXIN2 function and WNT signaling. Moreover, the modeling strategies used to demonstrate variant pathogenicity may be beneficial for the resolution of other de novo heterozygous variants of uncertain significance associated with congenital anomalies in humans. | Simkhada, B., Nazario-Yepiz, N. O., Freymuth, P. S., Lyman, R. A., Shankar, V., Wiggins, K., Flanagan-Steet, H., Basu, A., Weiss, R. J., Anholt, R. R. H., Mackay, T. F. C. (2025). A Drosophila model of mucopolysaccharidosis IIIB. Genetics, 229(3) PubMed ID: 39737777
Summary: Mucopolysaccharidosis type IIIB is a rare lysosomal storage disorder caused by defects in alpha-N-acetylglucosaminidase (NAGLU) and characterized by severe effects in the central nervous system. Mutations in NAGLU cause accumulation of partially degraded heparan sulfate in lysosomes. The consequences of these mutations on whole-genome gene expression and their causal relationships to neural degeneration remain unknown. This study used the functional Drosophila melanogaster ortholog of NAGLU, Naglu, to develop a fly model for MPS IIIB induced by gene deletion (NagluKO), missense (NagluY160C), and nonsense (NagluW422X) mutations. The Drosophila activity monitoring system was used to analyze activity and sleep. and sex- and age-dependent hyperactivity and sleep defects were found in mutant flies. Fluorescence microscopy on mutant fly brains using Lysotracker dye revealed a significant increase in acidic compartments. Differentially expressed genes determined from RNA sequencing of fly brains are involved in biological processes that affect nervous system development. A genetic interaction network constructed using known interacting partners of these genes consists of 2 major subnetworks, one of which is enriched in genes associated with synaptic function and the other with neurodevelopmental processes. The data indicate that lysosomal dysfunction arising from disruption of heparan sulfate breakdown has widespread effects on the steady state of intracellular vesicle transport, including vesicles associated with synaptic transmission. Evolutionary conservation of fundamental biological processes predicts that the Drosophila model of mucopolysaccharidosis type IIIB can serve as an in vivo system for the future development of therapies for mucopolysaccharidosis type IIIB and related disorders. |
| Bolshakova, O. I., Slobodina, A. D., Slepneva, E. E., Sarantseva, S. V. (2024). Acetyl-L-Carnitine Aids in Preservation of Cholinergic Neurons and Memory in the Drosophila melanogaster Model of Alzheimer's Disease. Curr Alzheimer Res, 21(8):557-565 PubMed ID: 39716786
Summary: The lack of effective therapy for the treatment of Alzheimer's disease demands both the search for new drugs and the reconsideration of already known substances currently used in other areas of medicine. Drosophila melanogaster offers the potential to model features of Alzheimer's disease, study disease mechanisms, and conduct drug screening. The purpose of this work was to analyze the neuroprotective properties of the drug "carnicetine", which is an acetylated form of the natural low molecular weight compound L-carnitine. The drug is able to cross the blood-brain barrier and is currently used as a means of improving cellular metabolism. Using tissue-specific drivers, direct expression of amyloid beta peptide (42 amino acids) was exhibited in certain groups of neurons in the Drosophila melanogaster brain, namely in dopaminergic and cholinergic neurons. The effect of acetyl-L-carnitine (carnicetine) on the death of these neurons and the memory of flies was analyzed. The expression of amyloid beta peptide in dopaminergic or cholinergic neurons resulted in neurodegeneration of cholinergic neurons in the Drosophila brain and memory impairment. The use of carnicetine added to animal food made it possible to treat these disorders. At the same time, no effect on dopaminergic neurons was noted. The data obtained confirmed the neuroprotective properties of the drug under study, demonstrating its participation in the restoration of the cholinergic system and the feasibility of using carnicetine for the treatment of Alzheimer's disease. | Strilbytska, O. M., Semaniuk, U., Yurkevych, I., Berezovskyi, V., Glovyak, A., Gospodaryov, D. V., Bayliak, M. M., Lushchak, O. (2024). 2,4-Dinitrophenol is toxic on a low caloric diet but extends lifespan of Drosophila melanogaster on nutrient-rich diets without an impact on metabolism. Biogerontology, 26(1):27 PubMed ID: 39702849
Summary: Uncouplers of mitochondrial electron transport chain, such as 2,4-dinitrophehol (DNP), can mimic calorie restriction by decreasing efficiency of adenosine triphosphate (ATP) synthesis. However, DNP is also a toxic substance, whose overdosage can be lethal. In the fruit fly, Drosophila melanogaster model, this study has found that DNP in concentrations of 0.05-0.1 g/L, led to a drastic decrease in fruit fly survival on a low caloric diet (1% sucrose and 1% yeast; 1S-1Y). On the 5S-5Y diet, DNP decreased lifespan of flies reared only in concentration 0.2 g/L, whilst on the diet 15S-15Y DNP either did not significantly shortened fruit fly lifespan or extended it. The lifespan extension on the high caloric 15S-15Y diet with DNP was accompanied by lower activity of lactate dehydrogenase and a decrease in activities of mitochondrial respiratory chain complexes I, II, and V, determined by blue native electrophoresis followed by in-gel activity assays. The exposure to DNP also did not affect key glycolytic enzymes, antioxidant and related enzymes, and markers of oxidative stress, such as aconitase activity and amount protein carbonyls. Consumption of DNP-supplemented diet did not affect flies' resistance to heat stress, though made male flies slightly more resistant to starvation compared with males reared on the control food. Substantial changes were not observed in the contents of metabolic stores, triacylglycerols and glycogen, in the DNP-treated flies. All this suggest that a nutrient-rich diets provide effective protection against DNP, providing a mild uncoupling of the respiratory chain that allows lifespan extension without considerable changes in metabolism. |
| Xia, D., Chen, Y., Fu, X., Liu, H. Y., Sun, M. Y., Wang, F., Zhang, Y., Liu, C. F., Liu, J. Y. (2025). Overexpression of α-synuclein in Pigment Dispersing Factor neurons alters sleep-wake pattern by regulating lipid metabolism in Drosophila. Sleep, 48(3) PubMed ID: 39707678
Summary: Parkinson's disease (PD) is a complex neurodegenerative disorder, characterized by the aggregation of α-synuclein (α-syn). Current research increasingly indicates the prevalence of sleep-wake disorders in early-stage PD, although the underlying pathogenic mechanisms remain unclear. In this study, transgenic Drosophila models were utilized to observe excessive daytime sleepiness and impaired anticipation in flies overexpressing α-syn in pan-neurons and circadian clock neurons. Additionally, deficits in projection of Pigment Dispersing Factor (PDF) neuron terminals, which are involved in Drosophila sleep and circadian rhythm, were identified. An imbalance in lipid metabolism homeostasis was detected in the brains of α-syn overexpressing mutants. Ultimately, the inhibition of Sterol Regulatory Element-Binding Protein (SREBP) activity led to an improvement in the reduced daytime sleep duration phenotype. The results suggest that lipid pathways play a role in sleep-wake disorders triggered by α-syn mutation and aggregation, thereby providing valuable insights into potential therapeutic avenues for disrupted sleep patterns associated with PD. | Qu, Q., Chen, Y., Wang, Y., Long, S., Wang, W., Yang, H. Y., Li, M., Tian, X., Wei, X., Liu, Y. H., Xu, S., Zhang, C., Zhu, M., Lam, S. M., Wu, J., Yun, C., Chen, J., Xue, S., Zhang, B., Zheng, Z. Z., Piao, H. L., Jiang, C., Guo, H., Shui, G., Deng, X., Zhang, C. S., Lin, S. C. (2025). Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature, 643(8070):192-200 PubMed ID: 39695227
Summary: Calorie restriction (CR) is a dietary intervention used to promote health and longevity. CR causes various metabolic changes in both the production and the circulation of metabolites(1); however, it remains unclear which altered metabolites account for the physiological benefits of CR. This study used metabolomics to analyse metabolites that exhibit changes in abundance during CR, and subsequent functional validation were performed. Lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, this study has identified that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner. |
Wednesday, October 14th - Genes, Enzymes, RNAs and Proteins - Expression, Evolution, Structure and Function |
| Zhang, T., Li, L., Fan, X., Shou, X., Ruan, Y., Xie, X. (2025). Metaxin-2 tunes mitochondrial transportation and neuronal function in Drosophila. Genetics, 229(2) PubMed ID: 39657051
Summary: Metaxins are a family of evolutionarily conserved proteins that reside on the mitochondria outer membrane (MOM) and participate in the protein import into the mitochondria. Metaxin-2 (Mtx2), a member of this family, has been identified as a key component in the machinery for mitochondrial transport in both C. elegans and human neurons. To deepen understanding of Mtx2's role in neurons, this study examined the homologous genes CG5662 and CG8004 in Drosophila. The CG5662 is a non-essential gene while CG8004 null mutants die at late pupal stages. The CG8004 protein is widely expressed throughout the Drosophila nervous system and is targeted to mitochondria. However, neuronal CG8004 is dispensable for animal survival and is partially required for mitochondrial distribution in certain neuropil regions. Conditional knockout of CG8004 in adult gustatory receptor neurons (GRNs) impairs mitochondrial trafficking along GRN axons and diminishes the mitochondrial quantities in axon terminals. The absence of CG8004 also leads to mitochondrial fragmentation within GRN axons, a phenomenon that may be linked to mitochondrial transport through its genetic interaction with the fusion proteins Marf and Opa1. While the removal of neuronal CG8004 is not lethal during the developmental stage, it does have consequences for the lifespan and healthspan of adult Drosophila. At last, double knockout (KO) of CG5662 and CG8004 shows similar phenotypes as the CG8004 single KO, suggesting that CG5662 does not compensate for the loss of CG8004. In summary, these findings suggest that CG8004 plays a conserved and context-dependent role in axonal mitochondrial transport, as well being important for sustaining neuronal function. Therefore, CG8004 is refered to as as the Drosophila Metaxin-2 (dMtx2). | Lempicki, C., Milosavljevic, J., Laggner, C., Tealdi, S., Meyer, C., Walz, G., Lang, K., Campa, C. C., Hermle, T. (2024). Discovery of a Small Molecule with an Inhibitory Role for RAB11. Int J Mol Sci, 25(23) PubMed ID: 39684933
Summary: RAB11, a pivotal RabGTPase, regulates essential cellular processes such as endocytic recycling, exocytosis, and autophagy. The protein was implicated in various human diseases, including cancer, neurodegenerative disorders, viral infections, and podocytopathies. However, a small-molecular inhibitor is lacking. The complexity and workload associated with potential assays make conducting large-scale screening for RAB11 challenging. A tiered approach for drug discovery was employed, utilizing deep learning-based computational screening to preselect compounds targeting a specific pocket of RAB11 protein with experimental validation by an in vitro platform reflecting RAB11 activity through the exocytosis of GFP. Further validation included the exposure of Drosophila by drug feeding. In silico pre-screening identified 94 candidates, of which 9 were confirmed using an in vitro platform for Rab11 activity. Focusing on compounds with high potency, autophagy, which independently requires RAB11 was assessed, and three of these compounds were validated. The dose-response relationship was further analyzed, observing a biphasic, potentially hormetic effect. Two candidate compounds specifically caused a shift in Rab11 vesicles to the cell periphery, without significant impact on Rab5 or Rab7. Drosophila larvae exposed to another candidate compound with predicted oral bioavailability exhibited minimal toxicity, subcellular dispersal of endogenous Rab11, and a decrease in RAB11-dependent nephrocyte function, further supporting an inhibitory role. Taken together, the combination of computational screening and experimental validation allowed the identification of small molecules that modify the function of Rab11. This discovery may further open avenues for treating RAB11-associated disorders. |
| Wang, Y., Chen, Q., Wu, C., Ding, Y., Yuan, L., Wang, Z., Chen, Y., Li, J., Liu, Z., Xiao, K., Liu, W. (2025). SASH1 is a novel binding partner to disassemble Caskin1 tandem SAM homopolymer through heterogeneous SAM-SAM interaction. Febs j, 292(7):1763-1780 PubMed ID: 39688081
Summary: Calcium/calmodulin-dependent serine protein kinase (CASK) interaction protein 1/2 (Caskin1/2) is essential neuronal synaptic scaffold protein in nervous system development. Knockouts of Caskin1/2 display severe deficits in novelty recognition and spatial memory. The tandem sterile alpha motif (SAM) domains of Caskin1/2, also conserved in their Drosophila homolog Ckn, are known to form homopolymers, yet their dynamic regulation mechanism remains unclear. In this study, SAM and SH3 domain-containing protein 1 (SASH1) was first identified as a novel binding partner of Caskin1/2 through yeast two-hybrid (Y2H) screening. The SAM-SAM interaction between SASH1 and Caskin1 was biochemically characterized by size-exclusion chromatography (SEC), isothermal titration calorimetry (ITC), and glutathione-S-transferase (GST) pull-down and co-immunoprecipitation (co-IP) assays. Structural insights from AlphaFold2-predicted models of the Caskin1-SAMs/SASH1-SAM1 complex, along with mutagenesis validations, revealed key residues at the end-helix (EH)/mid-loop (ML) interface for this interaction. More interestingly, the Caskin1-SAMs homopolymer can be disrupted by the SAM-SAM interaction, which was consistently verified by using sedimentation, transmission electron microscopy (TEM), and immunofluorescence (IF) staining in heterologous cell lines. In summary, these findings provide a solid biochemical basis for the Caskin1/SASH1 interaction and propose a potential mechanism for regulating Caskin1/2 homopolymerization via SAM-SAM interactions. More importantly, the principle governing SAM homopolymer depolymerization is generalized via suggesting two distinct types of heterogeneous SAM-SAM interactions, offering fresh insights into SAM domain-mediated homopolymerization and depolymerization. | Li, Y., Xu, Y., Li, R., Huang, S., Wu, Q., Yan, J., Jiang, Z., Wu, X., Li, F., Wang, Y., Li, Y., Fan, X., Yuan, W. (2024). Transcriptomic and Metabolomic Analysis Reveals Multifaceted Impact of Gcn5 Knockdown in Drosophila Development. Metabolites, 14(12) PubMed ID: 39728461
Summary: General control nonderepressible 5 (Gcn5) is a lysine acetyltransferase (KAT) that is evolutionarily conserved across eukaryotes, with two homologs (Kat2a and Kat2b) identified in humans and one (Gcn5) in Drosophila. Gcn5 contains a P300/CBP-associated factor (PCAF) domain, a Gcn5-N-acetyltransferase (GNAT) domain, and a Bromodomain, allowing it to regulate gene expression through the acetylation of both histone and non-histone proteins. In Drosophila, Gcn5 is crucial for embryonic development, with maternal Gcn5 supporting early development. However, the functional mechanisms of Gcn5 after the depletion of maternal deposits remain unclear. This study employed the Gal4/UAS-RNAi system to achieve whole-body or heart-specific Gcn5 knockdown in Drosophila and selected 96-hour-old surviving larvae for transcriptomic and metabolomic analyses. Omics results revealed that Gcn5 knockdown significantly impacts various metabolic pathways, as well as lysosomes, non-homologous end-joining, Toll and Imd signaling pathways, and circadian rhythms, among others. Furthermore, defects in chitin synthesis may be associated with impaired pupation. Additionally, heart-specific Gcn5 knockdown affected cardiac physiology but appeared to have a potential protective effect against age-related cardiac decline. These findings deepen understanding of Gcn5's roles in Drosophila development and provide valuable insights for developing Gcn5-targeted therapies, particularly considering its involvement in various human diseases. |
| Zhao, S., Jiang, X., Li, N., Wang, T. (2024). SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila. PLoS Biol, 22(12):e3002941 PubMed ID: 39680501
Summary: Phospholipids are critical building blocks of mitochondria, and proper mitochondrial function and architecture rely on phospholipids that are primarily transported from the endoplasmic reticulum (ER). This study shows that mitochondrial form and function rely on synthesis of phosphatidylserine (PS) in the ER through phosphatidylserine synthase (PSS), trafficking of PS from ER to mitochondria (and within mitochondria), and the conversion of PS to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase (PISD) in the inner mitochondrial membrane (IMM). Using a forward genetic screen in Drosophila, This study found that Slowmo(SLMO) specifically transfers PS from the outer mitochondrial membrane (OMM) to the IMM within the inner boundary membrane (IBM) domain. Thus, SLMO is required for shaping mitochondrial morphology, but its putative conserved binding partner, dTRIAP, is not. Importantly, SLMO's role in maintaining mitochondrial morphology is conserved in humans via the SLMO2 protein and is independent of mitochondrial dynamics. These results highlight the importance of a conserved PSS-SLMO-PISD pathway in maintaining the structure and function of mitochondria. | Kurshakova, M. M., Krasnov, A. N., Nabirochkina, E. N., Georgieva, S. G. (2024). [Drosophila melanogaster Paip2 Binds ENY2 and Interacts with the TREX-2 Complex in Histone mRNP Particles]. Mol Biol (Mosk), 58(3):448-461 PubMed ID: 39707855
Summary: ENY2 (enhancer of yellow 2, or e(y)2) is an evolutionarily conserved multifunctional protein and is a member of several complexes that regulate various stages of gene expression. ENY2 is a subunit of the TREX-2 complex, which is necessary for the export of bulk mRNA from the nucleus to the cytoplasm through the nuclear pores in many eukaryotes. The wide range of ENY2 functions suggests that it can also associate with other protein factors or complexes. In a search for proteins that interact with ENY2 of Drosophila melanogaster, a cDNA library was screened in a yeast two-hybrid system. ENY2 was thus found to interact with the RNA-binding protein Paip2. Paip2 directly bound ENY2 in vitro and interacted with ENY2 in vivo at the molecular and genetic levels. Paip2 was capable of association with the ENY2-containing TRANSCRIPTION EXPORT COMPLEX-2 (TREX-2) complex. Paip2 was present at the locus of the histone gene cluster. Both Paip2 and ENY2 were detected at histone locus body (HLBs), nuclear structure where coordinated histone mRNA transcription and processing take place. Paip2 and subunits of the TREX-2 complex were shown to associate with histone mRNP particles. A Paip2 knockdown via RNA interference resulted in decreased binding of TREX-2 subunits to histone mRNPs. Thus, Paip2 was identified as a new partner protein of ENY2 within the TREX-2 complex and suggested to participate in TREX-2 binding to histone mRNPs. |
Tuesday, October 13th - Behavior |
| Putilov, A. A., Verevkin, E. G., Petrovskii, D. V., Zakharenko, L. P. (2025). Bimodal Patterns of Locomotor Activity and Sleep in Drosophila: A Model for Their Simulation. J Nat Sci Sleep, 17:115-127 PubMed ID: 39845768
Summary: Two previously proposed modelling approaches to explain the bimodal pattern of activity and/or sleep in Drosophila melanogaster are based on 1) the concept of morning and evening oscillators underlying the peaks of activity in the morning and evening, respectively, and 2) the concept of two cycles of buildup and decay of sleep pressure, gated only by the circadian oscillator. Previously, 24-h alertness-sleepiness curves in humans were simulated using a model postulating the circadian modulation of the buildup and decay phases of two (wake and sleep) homeostatic processes. This study tested whether a similar model could be applied to simulate the bimodal 24-h rhythm of fly locomotor activity and sleep. To obtain typical curves for the simulations, a sample of 4263 individual 24-h curves of locomotor activity and sleep were subjected to principal component analysis. It yielded three principal components, which explained more than 70% of the individual variations in these curves. The typical curves using scores on the 1(st), 2(nd), and 3(rd) principal components and these curves and the sample-averaged curves were sumulated. These curves were found to be always characterized by two peaks with varying sizes and timings. They can be fitted by proposing the variation of some of the parameters of the two homeostatic processes reflecting the 24-h rhythmicity of the drive for wake and the 12-h rhythmicity of the drive for sleep. It is cocluded that postulation of two separate circadian oscillators is not necessary to explain the bimodal curves in Drosophila melanogaster. | Akpoghiran, O., Strich, A. K., Koh, K. (2024). Effects of sex, mating status, and genetic background on circadian behavior in Drosophila. bioRxiv, PubMed ID: 39605702
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, 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. |
| Vega-Trejo, R., Sanghvi, K., Todorova, B., Sepil, I., Bath, E. (2024). Fear of mating out (FOMO): voyeurism does not increase mating propensity in fruit flies. Sci Rep, 14(1):31916 PubMed ID: 39738633
Summary: Mate availability and social information can influence mating behaviour in both males and females. Social information obtained from conspecifics can influence mate choice, particularly shown by studies on mate choice copying. However, the role of directly observing conspecific mating on mating behaviour has been less explored. As such, whether conspecifics are copulating or not could inform 'observers' about the availability of mates, or even stimulate observers to mate themselves. Using Drosophila melanogaster, this study tested whether exposure to the visual cue of a mating pair would increase the mating propensity of an observer pair (i.e., voyeur). A factorial design was followed where a male-female pair (voyeur flies) were placed together with or without visual access to another pair of flies (who were either mating or not mating). No evidence was found that mating latency or duration of mating were affected by whether voyeurs had visual access to a mating or non-mating pair. These results could be due to biological factors (e.g., use of other non-visual cues by flies to acquire information related to sex), or methodological limitations of this study (e.g., flies unable to watch other pairs). Generally, these results suggest that fruit flies do not use visual cues from conspecifics mating to adjust their own mating latency or mating duration. | Hamamichi, K., Takahashi, Y. (2025). Stochastic variation in foraging traits within inbred lines of Drosophila. PloS one, 20(1):e0289864 PubMed ID: 39820056
Summary: Investigating the causes and consequences of niche partitioning in populations is a major goal in ecology and evolutionary biology. Previous studies have investigated genetic and environmentally induced variation in resource utility and their ecological implications. However, few studies have explored variability (non-genetic, stochastic variation) as a factor contributing to variation in resource utility. This study examined the variability in foraging traits of Drosophila lutescens, a species of wild fruit fly. Using 70 iso-female lines from a single population, we observed two foraging traits, i.e., locomotive speed and resource preferences, in an "8"-shaped experimental arena containing different types of fruit juices. The mean locomotive speed and relative preference for orange juice over grape juice varied significantly among iso-female lines. Additionally, the degree of intraline variation (variability) was detected a fold-change of larger than 2-fold between the smallest line and the largest line. While the mean locomotive speed itself did not correlate with mean resource preferences, the variability of locomotive speed significantly correlated with that of resource preferences. These results suggest that the degree of variability within inbred lines for both locomotive activity and resource preference is potentially partly genetic and that a shared genetic basis may govern variability in these traits. The variability of a particular trait is considered to interact cooperatively with the variability of several other traits in creating phenotypic intraspecific variation within a population. |
| De Nardo, A. N., Biswas, B., Perdigon Ferreira, J., Meena, A., Lupold, S. (2025). Socio-ecological context modulates the significance of territorial contest competition in Drosophila prolongata. Proceedings Biological sciences, 292(2039):20242501 PubMed ID: 39837512
Summary: The intensity and direction of sexual selection are intricately linked to the social and ecological context. Both operational sex ratios (OSRs) and population densities can affect the ability of males to monopolize resources and mates, and thus the form and intensity of sexual selection on them. This project studied how the mating system of the promiscuous and strongly sexually dimorphic fruit fly Drosophila prolongata responds to changes in the OSR and population density. Groups of flies were recorded over five days, and territory occupancy, mating success (MS) and competitive fertilization success were quantified. Although sexual selection was stronger under male-biased than even OSRs but unrelated to density, realized selection on morphological traits was higher under even OSRs and increased with density. Larger and more territorial males achieved both higher MS and competitive fertilization success, but only under even OSRs. The combined results also support a shift in the mating system from territorial contest competition to scramble competition under male-biased OSRs and potentially at low density, where there was no clear contribution of the measured traits to reproductive success. This study emphasizes the limitations of traditional selection metrics and the role of the socio-ecological context in predicting adaptation to a changing environment. | Freed, G. S., Martinez, I. G., Lev, A., Anthony Cuadrado, A. M., Pischedda, A. (2025). Genetic Variation in Male Mate Choice for Large Females in Drosophila melanogaster. Ecology and evolution, 15(1):e70794 PubMed ID: 39790727
Summary: Males in many species show courtship and mating preferences for certain females over others when given the choice. One of the most common targets of male mate choice in insects is female body size, with males preferring to court and mate with larger, higher-fecundity females and investing more resources in matings with those females. Although this preference is well-documented at the species level, less is known about how this preference varies within species and whether there is standing genetic variation for male mate choice within populations. Hemiclonal analysis in the fruit fly, Drosophila melanogaster, was used to test for heritable genetic variation in pre- and postcopulatory components of male mate choice for large females. Additive genetic variation was found for both forms of male choice: Males from different hemiclone lines varied in the strength of their courtship preferences for large females and the degree to which they extended matings with large females. Although males from hemiclone lines with stronger courtship preferences for large females were more likely to mate with those females, there was no genetic correlation between pre- and postcopulatory components of male mate choice, suggesting that they are under independent genetic control. Genetic variation in male mate choice may be widespread, potentially impacting the fitness of both sexes and the adaptive evolution of populations. |
Thursday October 8th - Adult neural structure, development, and function |
| Cruz, J., Urena, E., Iniguez, L. P., Irimia, M., Franch-Marro, X., Martin, D. (2024). E93 controls adult differentiation by repressing broad in Drosophila. Proc Natl Acad Sci U S A, 121(51):e2403162121 PubMed ID: 39671182
Summary: In Drosophila melanogaster, successful development relies on the precise coordination of both spatial and temporal regulatory axes. The temporal axis governs stage-specific identity and developmental transitions through a number of genes, collectively forming the Metamorphic Gene Network. Among these, Ecdysone inducible protein 93F (E93) serves as the critical determinant for adult specification, but its mechanism of action remains unclear. This study found that, rather than acting mainly as an instructive signal, E93 promotes adult differentiation through the repression of the pupal specifier broad (br). In the absence of E93, sustained high levels of Br during the pupal stage strongly represses pupal-specific enhancers that are essential for the terminal differentiation of the wing. Notably, RNA-seq analysis confirmed that the majority of E93-dependent transcriptomic changes in pupal wings are primarily driven by br repression. In addition, it was also shown that Br represses the pupal-enhancers during the larval and prepupal stages preventing the premature implementation of the adult genetic program, and it also dampens the activity of larval enhancers during the latter stages of larval development. This mechanism of action seems to be a derived feature acquired in Diptera, as in the coleopteran Tribolium castaneum, repression of br by E93 is not sufficient to allow adult differentiation. In summary, this study elucidates the crucial role of the intricate interplay between E93 and Br as the governing mechanism in the process of terminal differentiation in Drosophila. This finding holds significant implications for advancing understanding of the evolution of insect metamorphosis. | Zipper, L., Corominas-Murtra, B., Reiff, T. (2025). Steroid hormone-induced wingless ligands tune female intestinal size in Drosophila. Nature communications, 16(1):436 PubMed ID: 39762218
Summary: Female reproduction comes at great expense to energy metabolism compensated by extensive organ adaptations including intestinal size. Upon mating, endocrine signals orchestrate a 30% net increase of absorptive epithelium. Mating increases production of the steroid hormone Ecdysone released by the Drosophila ovaries that stimulates intestinal stem cell (ISC) divisions. This study uncoverec the transcription factor crooked legs (crol) as an intraepithelial coordinator of Ecdysone-induced ISC mitosis. For the precise investigation of non-autonomous factors on ISC behaviour, this study established Rapport, a spatiotemporally-controlled dual expression and tracing system for the analysis of paracrine genetic manipulation while tracing ISC behaviour. Rapport tracing reveals that Ecdysone-induced Crol controls mitogenic Wnt/Wg-ligand expression from epithelial enterocytes activating ISC mitosis. Paracrine Wg stimulation is counterbalanced by Crol-repression of string/CDC25 and CyclinB autonomously in ISC. Rapport-based ISC tumours confirm paracrine stimulation through the Ecdysone-Crol-Wg axis on mitotic behaviour, whereas the autonomous anti-proliferative role of Crol in ISC is conserved in models of colorectal cancer. Finally, mathematical modelling corroborates increasing enterocyte numbers and Wnt/Wg-degradation to set a stable post-mating intestinal size. Together, these findings provide insights into the complex endocrine growth control mechanisms during mating-induced adaptations and might help untangling pleiotropic hormonal effects observed in gastrointestinal tumorigenesis. |
| Ramesh, N. A., Box, A. M., Buttitta, L. A. (2025). Post-eclosion growth in the Drosophila ejaculatory duct is driven by Juvenile hormone signaling and is essential for male fertility. Dev Biol, 519:122-141 PubMed ID: 39719194
Summary: The Drosophila Ejaculatory duct (ED) is a secretory tissue of the somatic male reproductive system. The ED is involved in the secretion of seminal fluid components and ED-specific antimicrobial peptides that aid in fertility and the female post-mating response. The ED is composed of secretory epithelial cells surrounded by a layer of innervated contractile muscle. The ED grows in young adult males during the first 24 h post-eclosion, but the cell cycle status of the ED secretory cells and the role of post-eclosion ED growth have been unexplored. This study shows that secretory cells of the adult Drosophila ED undergo variant cell cycles lacking mitosis called the endocycle, that lead to an increase in the cell and organ size of the ED post eclosion. The cells largely exit the endocycle by day 3 of adulthood, when the growth of the ED ceases, resulting in a tissue containing cells of ploidies ranging from 8C to 32C. The size of the ED directly correlates with the ploidy of the secretory cells, with additional ectopic endocycles increasing organ size. When endoreplication is compromised in ED secretory cells, it leads to reduced organ size, reduced protein synthesis and compromised fertility. Evidence is provided that the growth and endocycling in the young adult male ED is dependent on Juvenile hormone (JH) signaling and it is suggested that hormone-induced early adult endocycling is required for optimal fertility and function of the ED tissue. The authors intend to use the ED as a post-mitotic tissue model to study the role of polyploidy in regulating secretory tissue growth and function. | Rohith, B. N., Gogia, N., Rai, A., Singh, A., Kango-Singh, M. (2026). Hippo signaling regulates dorsoventral patterning in Drosophila head and eye development. iScience, 29(10):117585 PubMed ID: 42823957
Summary: The integration of growth and patterning is essential for proper tissue development. In Drosophila, the Hippo pathway controls organ size, including formation of adult structures from the eye-antennal imaginal disc. Defective Proventriculus (Dve), a K-50 domain transcription factor, regulates dorsal-ventral patterning by suppressing eye fate and promoting head cuticle development, thereby influencing eye position and interocular distance. We investigated how the Hippo effector Yorkie (Yki) and Dve coordinate growth and patterning in the dorsal head region. Our results show that Yki regulates dorsal head size, while Dve suppresses Yki in this region. Yki also controls dorsal-ventral patterning genes, including pnr, wg, and mirr, to coordinate eye and head development. Because mammalian orthologs of yki, dve, pnr, and wg are linked to developmental disorders such as facial dysmorphia, our findings reveal conserved mechanisms connecting growth, patterning, and craniofacial development across species, with potential relevance to human developmental disease and tissue morphogenesis. |
| Kharazmi, J., Brody, T., Moshfegh, C. (2026) . Functional dissection of Drosophila Myc cis -regulatory modules (Myc-CRMs) reveals developmentally active DNA-protein interactions. bioRxiv, PubMed ID: 42818484
Summary: Precise regulation of Drosophila Myc is essential for growth and homeostasis, yet regulation of its transcriptional control remains incompletely understood. This study investigated the Myc cis -regulatory landscape using in vivo reporter assays, EMSA, and LC-MS/MS-based identification of DNA-associated proteins. By truncating Myc cis -regulatory modules (CRMs), this study delineated the activity of conserved non-coding elements across adult female tissues and larval stages. Specific DNA-protein interactions were confirmed by EMSA using nuclear embryonic extracts. A Solid Surface Magnetic Enrichment protocol (SSMEP) was developed to pull down DNA-protein complexes formed on Myc cis -elements. Affinity purification followed by LC-MS/MS enabled the identification of candidate transcriptional regulators associated with Myc-CRMs. This integrative approach provides new insights into promoter structure and trans-regulatory architecture of Myc and their roles in developmental gene expression programs. This study identifies a distal enhancer required for larval and pupal patterning, with activation dependent on specific spacing relative to the TATA-box core promoter, a strong enhancer cluster within 5'-UTR cis -elements active in ovaries and embryos, and a DPE-core promoter requiring nearby enhancer action. The DPE-linked enhancer can function with both Inr-DPE and TATA-box promoters. The identified Myc-CRMs interact with conserved signaling pathways to tightly control Myc during development. | Ramesh, N. A., Box, A. M., Buttitta, L. A. (2025). Post-eclosion growth in the Drosophila ejaculatory duct is driven by Juvenile hormone signaling and is essential for male fertility. Dev Biol, 519:122-141 PubMed ID: 39719194
Summary: The Drosophila Ejaculatory duct (ED) is a secretory tissue of the somatic male reproductive system. The ED is involved in the secretion of seminal fluid components and ED-specific antimicrobial peptides that aid in fertility and the female post-mating response. The ED is composed of secretory epithelial cells surrounded by a layer of innervated contractile muscle. The ED grows in young adult males during the first 24 h post-eclosion, but the cell cycle status of the ED secretory cells and the role of post-eclosion ED growth have been unexplored. This study shows that secretory cells of the adult Drosophila ED undergo variant cell cycles lacking mitosis called the endocycle, that lead to an increase in the cell and organ size of the ED post eclosion. The cells largely exit the endocycle by day 3 of adulthood, when the growth of the ED ceases, resulting in a tissue containing cells of ploidies ranging from 8C to 32C. The size of the ED directly correlates with the ploidy of the secretory cells, with additional ectopic endocycles increasing organ size. When endoreplication is compromised in ED secretory cells, it leads to reduced organ size, reduced protein synthesis and compromised fertility. Evidence is provided that the growth and endocycling in the young adult male ED is dependent on Juvenile hormone (JH) signaling and it is suggested that hormone-induced early adult endocycling is required for optimal fertility and function of the ED tissue. The authors intend to use the ED as a post-mitotic tissue model to study the role of polyploidy in regulating secretory tissue growth and function. |
Thursday October 8th - Adult neural structure, development, and function |
| Pang, M. M., Chen, F., Xie, M., Druckmann, S., Clandinin, T. R., Yang, H. H. (2025). A recurrent neural circuit in Drosophila temporally sharpens visual inputs. Curr Biol, 35(2):333-346.e336 PubMed ID: 39706173
Summary: A critical goal of vision is to detect changes in light intensity, even when these changes are blurred by the spatial resolution of the eye and the motion of the animal. This study describes a recurrent neural circuit in Drosophila that compensates for blur and thereby selectively enhances the perceived contrast of moving edges. Using in vivo, two-photon voltage imaging, the temporal response properties were measured of L1 and L2, two cell types that receive direct synaptic input from photoreceptors. These neurons have biphasic responses to brief flashes of light, a hallmark of cells that encode changes in stimulus intensity. However, the second phase was often much larger in area than the first, creating an unusual temporal filter. Genetic dissection revealed that recurrent neural circuitry strongly shapes the second phase of the response, informing the structure of a dynamical model. By applying this model to moving natural images, it was demonstrated that rather than veridically representing stimulus changes, this temporal processing strategy systematically enhances them, amplifying and sharpening responses. Comparing the measured responses of L2 to model predictions across both artificial and natural stimuli revealed that L2 tunes its properties as the model predicts to temporally sharpen visual inputs. Since this strategy is tunable to behavioral context, generalizable to any time-varying sensory input, and implementable with a common circuit motif, it could be broadly used to selectively enhance sharp and salient changes. | Gregory, E. S., Xu, Y. Y. J., Lee, T. T., Joiner, M. A., Kamikouchi, A., Su, M. P., Eberl, D. F. (2025). The Voltage-Gated Potassium Channel Shal (K(v)4) Contributes to Active Hearing in Drosophila. eNeuro, 12(1) PubMed ID: 39689967
Summary: The full complement of ion channels which influence insect auditory mechanotransduction and the mechanisms by which their influence is exerted remain unclear. Shal (K(v)4), a Shaker family member encoding voltage-gated potassium channels in Drosophila melanogaster, has been shown to localize to dendrites in some neuron types, suggesting the potential role of Shal in Drosophila hearing, including mechanotransduction. A GFP trap was used to visualize the localization of the Shal channel in Johnston's organ neurons responsible for hearing in the antenna. Shal protein was localized strongly to the cell body and inner dendritic segment of sensory neurons. It was also detectable in the sensory cilium, suggesting its involvement not only in general auditory function but specifically in mechanotransduction. Electrophysiological recordings to assess neural responses to auditory stimuli in mutant Shal flies revealed significant decreases in auditory responses. Laser Doppler vibrometer recordings indicated abnormal antennal free fluctuation frequencies in mutant lines, indicating an effect on active antennal tuning, and thus active transduction mechanisms. This suggests that Shal participates in coordinating energy-dependent antennal movements in Drosophila that are essential for tuning the antenna to courtship song frequencies. |
| Zheng, T., Long, K., Wang, S., Rui, M. (2025). Glial-derived TNF/Eiger signaling promotes somatosensory neurite sculpting. Cell Mol Life Sci, 82(1):47 PubMed ID: 39833565
Summary: The selective elimination of inappropriate projections is essential for sculpting neural circuits during development. The class IV dendritic arborization (C4da) sensory neurons of Drosophila remodel the dendritic branches during metamorphosis. Glial cells in the central nervous system (CNS), are required for programmed axonal pruning of mushroom body (MB) γ neurons during metamorphosis in Drosophila. However, it is entirely unknown whether the glial cells are involved in controlling the neurite pruning of C4da sensory neurons. This study shows that glial deletion of Eiger (Egr), orthologous to mammalian tumor necrosis factor TNF superfamily ligand, results in dendrite remodeling deficiency of Drosophila C4da sensory neurons. Moreover, the attenuation of neuronal Wengen (Wgn) and Grindelwald (Grnd), the receptors for TNF ligands, is also examined for defects in dendrite remodeling. It was further discovered that Wgn and Grnd facilitate dendrite elimination through the JNK Signaling. Overall, these findings demonstrate that glial-derived Egr signal links to the neuronal receptor Wgn/Grnd, activating the JNK signaling pathway and promoting developmental neuronal remodeling. Remarkably, these findings reveal a crucial role of peripheral glia in dendritic pruning of C4da neurons. | Lehmann, K. S., Hupp, M. T., Abalde-Atristain, L., Jefferson, A., Cheng, Y. C., Sheehan, A. E., Kang, Y., Freeman, M. R. (2025). Astrocyte-dependent local neurite pruning in Beat-Va neurons. J Cell Biol, 224(1) PubMed ID: 39652106
Summary: Developmental neuronal remodeling is extensive and mechanistically diverse across the nervous system. This study sought to identify Drosophila pupal neurons that underwent mechanistically new types of neuronal remodeling and describes remodeling Beat-VaM and Beat-VaL neurons. cBeat-VaM neurons produce highly branched neurites in the CNS during larval stages that undergo extensive local pruning. Surprisingly, although the Ecdysone receptor (EcR) is essential for pruning in all other cell types studied, Beat-VaM neurons (medial neurons expressing Beat-Va) remodel their branches extensively despite cell autonomous blockade ccEcR (Ceratitis capitata EcR) or caspase signaling. Proper execution of local remodeling in Beat-VaM neurons instead depends on extrinsic signaling from astrocytes converging with intrinsic and less dominant EcR-regulated mechanisms. In contrast, Beat-VaL neurons (lateral Beat-Va neurons) undergo steroid hormone-dependent, apoptotic cell death, which this study shows relies on the segment-specific expression of the Hox gene Abd-B. This work provides new cell types in which to study neuronal remodeling, highlights an important role for astrocytes in activating local pruning in Drosophila independent of steroid signaling, and defines a Hox gene-mediated mechanism for segment-specific cell elimination. |
| Jeong, J., Kwon, K., Geisseova, T. K., Lee, J., Kwon, T., Lim, C. (2024). Drosulfakinin signaling encodes early-life memory for adaptive social plasticity. JElife, 13 PubMed ID: 39692597
Summary: Drosophila establishes social clusters in groups, yet the underlying principles remain poorly understood. This study performed a systemic analysis of social network behavior (SNB) that quantifies individual social distance (SD) in a group over time. The SNB assessment in 175 inbred strains from the Drosophila Genetics Reference Panel showed a tight association of short SD with long developmental time, low food intake, and hypoactivity. The developmental inferiority in short-SD individuals was compensated by their group culturing. By contrast, developmental isolation silenced the beneficial effects of social interactions in adults and blunted the plasticity of SNB under physiological challenges. Transcriptome analyses revealed genetic diversity for SD traits, whereas social isolation reprogrammed select genetic pathways, regardless of SD phenotypes. In particular, social deprivation suppressed the expression of the neuropeptide Drosulfakinin (Dsk) in three pairs of adult brain neurons. Male-specific DSK signaling to Cholecystokinin-like receptor 17D1 mediated the SNB plasticity. In fact, transgenic manipulations of the DSK neuron activity were sufficient to imitate the state of social experience. Given the functional conservation of mammalian Dsk homologs, it is proposed that animals may have evolved a dedicated neural mechanism to encode early-life experience and transform group properties adaptively. | Avetisyan, A., Barria, R., Sheehan, A., Freeman, M. R. (2024). An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration. bioRxiv, PubMed ID: 39651259
Summary: How neurons to sense when they are terminally dysfunctional and activate neurodegeneration remains poorly defined. The pro-degenerative NAD (+) hydrolase dSarm/SARM1 can act as a metabolic sensor by detecting pathological changes in NAD (+) /NMN and subsequently induce catastrophic axon degeneration. This study shows Drosophila with-no-lysine kinase (dWnk), which can directly sense Cl- , K+ and osmotic pressure, is required for neurodegeneration induced by depletion of the NAD (+) biosynthetic enzyme dNmnat. dWnk functions in parallel to dSarm and acts through the downstream kinase Frayed to promote axon degeneration and neuronal cell death. dWnk and dSarm ultimately converge on the BTB-Back domain molecule Axundead (Axed) to execute neurodegeneration. This work argues that neurons use direct sensors of both metabolism (dSarm/SARM1) and ionic/osmotic status (dWnk) to evaluate cellular health and, when dysfunctional, promote neurodegeneration though a common axon death signaling molecule, Axundead. |
Tuesday October 6th - Immune Response |
| Kumar, S., D'Souza, L. C., Shaikh, F. H., Rathor, P., Ratnasekhar, C. H., Sharma, A. (2025). Multigenerational immunotoxicity assessment: A three-generation study in Drosophila melanogaster upon developmental exposure to triclosan. Environ Pollut, 370:125860 PubMed ID: 39954761
Summary: Triclosan (TCS) is widely used as an antibacterial agent, nevertheless, its presence in different environmental matrices and its persistent environmental nature pose a significant threat to the organism, including humans. Numerous studies showed that TCS exposure could lead to multiple toxicities, including immune dysfunction. However, whether parental TCS exposure could impair the offspring's immune response remains limited. This study aimed to assess the multigenerational immune response of TCS using Drosophila melanogaster. TCS was administered to organisms (1.0, 10, and 100.0 μg/mL) over three generations during their developing phases, and its effect on the immunological response of the unexposed progeny was evaluated. Total circulatory hemocyte (immune cells) count, crystal cell count, phagocytic activity, clotting time, gene expression related to immune response and epigenetics, ROS generation, and cell death were assessed in the offspring. A concentration-dependent decline in total hemocytes, crystal cells, phagocytic activity, and increased clotting time in the subsequent generations was observed. Furthermore, parental TCS exposure enhanced the ROS levels, induced cell death, and altered the expression of antimicrobial peptides drosomycin, diptericin, and inflammatory genes upd1, upd2, and upd3, in the offspring's hemocytes across successive generations. The upregulation of reaper hid, and grim suggests that TCS promotes apoptotic death in the offspring's hemocytes. Notably, the increased mRNA expression of epigenetic regulators dnmt2 and g9a in the hemocytes of the offspring indicates epigenetic modifications. Further, we also observed that the antioxidant N-acetylcysteine (NAC) supplementation to the parents alleviated TCS toxicity and improved immunological functions in the progeny, indicating the role of ROS in the TCS-induced multigenerational immune toxicity. This finding provides valuable insights into the potential immune risk of prenatal TCS exposure to their offspring in the higher organism. | Jalovecka, M., Malandrin, L., Urbanova, V., Mahmood, S., Snebergerova, P., Peklanska, M., Pavlasova, V., Sima, R., Kopacek, P., Perner, J., Hajdusek, O. (2024). Activation of the tick Toll pathway to control infection of Ixodes ricinus by the apicomplexan parasite Babesia microti. PLoS Pathog, 20(12):e1012743 PubMed ID: 39680508
Summary: The vector competence of blood-feeding arthropods is influenced by the interaction between pathogens and the immune system of the vector. The Toll and IMD (immune deficiency) signaling pathways play a key role in the regulation of innate immunity in both the Drosophila model and blood-feeding insects. However, in ticks (chelicerates), immune determination for pathogen acquisition and transmission has not yet been fully explored. This study has mapped homologs of insect Toll and IMD pathways in the European tick Ixodes ricinus, an important vector of human and animal diseases. Most genes of the Toll pathway are well conserved, whereas the IMD pathway has been greatly reduced. Therefore this study investigated the functions of the individual components of the tick Toll pathway; unlike in Drosophila, the Toll pathway was specifically activated by Gram-negative bacteria. The activation of pathway induced the expression of defensin (defIR), the first identified downstream effector gene of the tick Toll pathway. Borrelia, an atypical bacterium and causative agent of Lyme borreliosis, bypassed Toll-mediated recognition in I. ricinus and also resisted systemic effector molecules when the Toll pathway was activated by silencing its repressor cactus via RNA interference. Babesia, an apicomplexan parasite, also avoided Toll-mediated recognition. Strikingly, unlike Borrelia, the number of Babesia parasites reaching the salivary glands during tick infection was significantly reduced by knocking down cactus. The simultaneous silencing of cactus and dorsal resulted in greater infections and underscored the importance of tick immunity in regulating parasite infections in these important disease vectors. |
| Tang, G., Song, S., Shang, J., Luo, Y., Li, S., Wei, D., Wang, C. (2025). Fungal evasion of Drosophila immunity involves blocking the cathepsin-mediated cleavage maturation of the danger-sensing protease. Proceedings of the National Academy of Sciences, 122(3):e2419343122 PubMed ID: 39819219
Summary: Entomopathogenic fungi play a critical role in regulating insect populations, and representative species from the Metarhizium and Beauveria genera have been developed as eco-friendly biocontrol agents for managing agricultural insect pests. Relative to the advances in understanding antifungal immune responses in Drosophila, knowledge of how fungi evade insect immune defenses remains limited. This study reports the identification and characterization of a virulence-required effector Fkp1 in Metarhizium robertsii. Library screening and protein pull-down analysis unveiled that Fkp1 targets the cathepsin protease CtsK1 to inhibit its cleavage maturation of the danger-sensing serine protease Persephone (Psh), thereby facilitating fungal evasion of the Drosophila immune defenses. The Fkp1-like gene is also required in Beauveria bassiana for insect infection. Transgenic expression of Fkp1 in Drosophila suppressed hemolymph cysteine protease activity and down-regulated the expression of antifungal genes. Fkp1 can also mask the Psh cleavage site without interfering with its ability to bait fungal subtilisin proteases. Given the evident compensatory relationship, these data indicate that the protease cascade is more crucial than the molecular pattern pathway in defending flies against fungal infections. This work reveals that Metarhizium fungi have evolved distinct effectors to block the dual recognition pathways of flies for immune evasion and sheds lights on the effector mechanisms mediating microbe-animal interactions. | Singh, D. N. D., Roberts, A. R. E., Wang, X., Li, G., Quesada Moraga, E., Alliband, D., Ballou, E., Tsai, H. J., Hidalgo, A. (2025). Toll-1-dependent immune evasion induced by fungal infection leads to cell loss in the Drosophila brain. PLoS Biol, 23(2):e3003020 PubMed ID: 39946503
Summary: Fungi can intervene in hosts' brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFkappaB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. This study shows that exposure to the fungus Beauveria bassiana reduced fly life span, impaired locomotion and caused neurodegeneration. Beauveria bassiana entered the Drosophila brain and induced the up-regulation of AMPs, and the Toll adaptors wek and sarm, within the brain. RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana-induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause neuronal loss in the absence of infection. Thus, B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans. |
| Ai, X., Deng, H., Li, X., Wei, Z., Chen, Y., Yin, T., Zhang, J., Huang, J., Li, H., Lin, X., Tan, L., Chen, D., Zhang, X., Zhang, X., Meignin, C., Imler, J. L., Cai, H. (2024). cGAS-like receptors drive a systemic STING-dependent host response in Drosophila. Cell Rep, 43(12):115081 PubMed ID: 39688951
Summary: cGAS-like receptor (cGLR)-stimulator of interferon genes (STING) recently emerged as an important pathway controlling viral infections in invertebrates. However, its exact contribution at the organismal level remains uncharacterized. This study use STING::GFP knockin reporter Drosophila flies to document activation of the pathway in vivo. Four tissues strongly respond to injection of the cyclic dinucleotide 3'2'- cyclic guanosine monophosphate-adenosine monophosphate (cGAMP): the central nervous system, midgut, Malpighian tubules, and genital ducts. The pattern of STING::GFP induction in flies injected with 3'2'-cGAMP or infected by two viruses with different tropism suggests that the reporter is induced by a systemic signal produced in virus-infected cells. Accordingly, ectopic expression of cGLR2 in the fat body induces STING signaling in remote tissues and a cGLR1/2-dependent activity is transferred to females during mating. Furthermore, viral infection can alter sleep in a cGLR1/2- and STING-dependent manner. Altogether, these results reveal a contribution of cyclic dinucleotide signaling to a systemic host response to viral infection in Drosophila. | Oi, A., Shinoda, N., Nagashima, S., Miura, M., Obata, F. (2025). A nonsecretory antimicrobial peptide mediates inflammatory organ damage in Drosophila renal tubules. Cell Rep, 44(1):115082 PubMed ID: 39719708
Summary: An excessive immune response damages organs, yet its molecular mechanism is incompletely understood. A factor mediating organ damage upon genetic activation of the innate immune pathway was discovered using Drosophila renal tubules. An antimicrobial peptide, Attacin-D (AttD), causes organ damage upon immune deficiency (Imd) pathway activation in the Malpighian tubules. Loss of AttD function suppresses most of the pathological phenotypes induced by Imd activation, such as cell death, bloating of the whole animal, and mortality, without compromising the immune activation. AttD is required for the immune-induced damage specifically in the Malpighian tubules and not the midgut. Unlike other antimicrobial peptides, AttD lacks a signal peptide and stays inside tubular cells, potentially damaging the tubular cells via aggregation and oligomerization. Suppression of AttD almost completely attenuates the pathology caused by a gut-tumor-induced immune activation. This study elucidates the mechanistic effector of immune-induced organ damage. |
Monday October 5th - Synapse and Vesicles |
| Vicidomini, R., Han, T. H., Hsieh, W. C., Nguyen, P., Li, J., Giniger, E., Serpe, M. (2026). Integration of Semaphorin/Plexin activation and amplification by a Neuropilin-like coreceptor ensures robust homeostatic plasticity. Proc Natl Acad Sci U S A, 123(37):e2604252123 PubMed ID: 42709818
Summary: Robust homeostatic plasticity is essential for survival, enabling neuronal circuits to withstand destabilizing forces and restore function during critical challenges such as predator evasion or toxin exposure. Semaphorin/Plexin signaling is central to presynaptic homeostatic potentiation at central synapses and at neuromuscular junctions across species. However, understanding of this pathway has remained incomplete, as secreted Semaphorins bind weakly to their Plexin receptors and require additional coreceptors for efficient signaling. This study identified Neuropilin and Tolloid-like protein (Neto-alpha), an auxiliary subunit for ionotropic glutamate receptors (iGluRs), and the tyrosine kinase Abelson (Abl) as essential components of the Sema2b/PlexB signaling pathway that drives rapid homeostatic potentiation and stabilizes synaptic strength at the Drosophila neuromuscular junction. Neto-alpha functions as a Neuropilin-like coreceptor that cooperates with Sema2b to relieve PlexB autoinhibition and initiate signaling. In parallel, Neto-alpha recruits Abl, which functions as a cytosolic amplifier to enhance pathway output. Both pathway activation and amplification are required for a rapid and effective homeostatic response. By integrating these two functions within a single molecular assembly, Neto-alpha ensures fast and efficient compensatory responses to perturbations. This evolutionarily conserved signaling module, Neto (or Neuropilin)/Sema/Plex/Abl, likely operates in cellular contexts beyond neural function, including in tumorigenesis. | Neisch, A. L., Pengo, T., Avery, A. W., Li, M. G., Hays, T. S. (2025). Dynein-driven regulation of postsynaptic membrane architecture and synaptic function. Journal of cell science, 138(5) PubMed ID: 39865922
Summary: Cytoplasmic dynein is essential in motor neurons for retrograde cargo transport that sustains neuronal connectivity. Little, however, is known about dynein function on the postsynaptic side of the circuit. This study reports distinct postsynaptic roles for dynein at neuromuscular junctions in Drosophila. Intriguingly, show that dynein puncta accumulate postsynaptically at glutamatergic synaptic terminals. Moreover, Skittles (Sktl), a phosphatidylinositol 4-phosphate 5-kinase that produces phosphatidylinositol 4,5-bisphosphate (PIP2), was shown to organize the spectrin cytoskeleton, also localizes specifically to glutamatergic synaptic terminals. Depletion of postsynaptic dynein disrupted the accumulation of Skittles and the PIP2 phospholipid, and organization of the spectrin cytoskeleton at the postsynaptic membrane. Coincidental with dynein depletion, an increase was observed in the size of ionotropic glutamate receptor (iGluR) fields and an increase in the amplitude and frequency of miniature excitatory junctional potentials. PIP2 levels did not affect iGluR clustering, nor did dynein affect the levels of iGluR subunits at the neuromuscular junction. These observations suggest a separate, transport-independent function for dynein in iGluR cluster organization. Based on the close apposition of dynein puncta to the iGluR fields, iy is speculated that dynein at the postsynaptic membrane contributes to the organization of the receptor fields, hence ensuring proper synaptic transmission. |
| Lutzkendorf, J., Matkovic-Rachid, T., Liu, S., Gotz, T., Gao, L., Turrel, O., Maglione, M., Grieger, M., Putignano, S., Ramesh, N., Ghelani, T., Neumann, A., Gimber, N., Schmoranzer, J., Stawrakakis, A., Brence, B., Baum, D., Ludwig, K., Heine, M., Mielke, T., Liu, F., Walter, A. M., Wahl, M. C., Sigrist, S. J. (2025). Blobby is a synaptic active zone assembly protein required for memory in Drosophila. Nature communications, 16(1):271 PubMed ID: 39747038
Summary: At presynaptic active zones (AZs), scaffold proteins are critical for coordinating synaptic vesicle release and forming essential nanoarchitectures. However, regulatory principles steering AZ scaffold assembly, function, and plasticity remain insufficiently understood. This study identified an additional Drosophila AZ protein, "Blobby", essential for proper AZ nano-organization. Blobby biochemically associates with the ELKS family AZ scaffold protein Bruchpilot (BRP) and integrates into newly forming AZs. Loss of blobby results in fewer AZs forming, ectopic AZ scaffold protein accumulations ("blobs") and disrupts nanoscale architecture of the BRP-AZ scaffold. Functionally, blobby mutants show diminished evoked synaptic currents due to reduced synaptic vesicle release probability and fewer functional release sites. Blobby is also present in adult brain synapses, and post-developmental knockdown of Blobby in the mushroom body impairs olfactory aversive memory consolidation. Thus, this analysis identifies an additional layer of AZ regulation critical for developmental AZ assembly but also for AZ-mediated plasticity controlling behavior. | Ochi, Y., Yamashita, H., Sasaki, S., Ogawa, T., Yamada, Y., Tago, T., Satoh, T., Satoh, A. K. (2024). Comprehensive study of SNAREs involved in the post-Golgi transport in Drosophila photoreceptors. Front Cell Dev Biol, 12:1442192 PubMed ID: 39720007
Summary: Polarized transport is essential for the construction of multiple plasma membrane domains within cells. Drosophila photoreceptors serve as excellent model systems for studying the mechanisms of polarized transport. A comprehensive soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) screening of the fly genome using RNAi knockdown and CRISPR/Cas9 somatic knockout combined with the CoinFLP system was conducted to identify SNAREs involved in post-Golgi trafficking. The results suggest that in post-Golgi transport, no SNARE is exclusively responsible for transport to a single specific plasma membrane domain. However, each SNARE shows some preference for certain membrane domains: the loss of nSyb, Ykt6, and Snap24/25 results in severe defects in rhabdomere transport, while the loss of Syx1A and Snap29 leads to significant impairments in basolateral transport. Together with the function of Syx1A, Snap25, and nSyb in the fusion of synaptic vesicles with the synaptic plasma membrane, these results suggest that SNAREs are not the sole determinants for vesicles to specify their target subdomains in the plasma membrane. Furthermore, rhodopsin transport to the rhabdomere requires two kinds of R-SNAREs, Ykt6 and nSyb, suggesting that multiple sets of post-Golgi SNAREs contribute in tandem or in cooperation, rather than in parallel. |
| Kurogi, Y., Mizuno, Y., Hayashi, R., Goyins, K., Okamoto, N., Barton, L., Niwa, R. (2024). The seminal vesicle is a juvenile hormone-responsive tissue in adult male Drosophila melanogaster. Open Biol, 14(12):240315 PubMed ID: 39689858
Summary: Juvenile hormone (JH) is one of the most essential hormones controlling insect metamorphosis and physiology. While it is well known that JH affects many tissues throughout the insect life cycle, the difference in JH responsiveness and the repertoire of JH-inducible genes among different tissues has not been fully investigated. This study monitored JH responsiveness in vivo using transgenic Drosophila melanogaster flies carrying a JH response element-GFP (JHRE-GFP) construct. The data highlight the high responsiveness of the epithelial cells within the seminal vesicle, a component of the male reproductive tract, to JH. Specifically, an elevation in the JHRE-GFP signal within the seminal vesicle epithelium was observed upon JH analogue administration, while suppression occurs upon knockdown of a gene encoding the intracellular JH receptor, germ cell-expressed. Starting from published transcriptomic and proteomics datasets, Lactate dehydrogenase was identified as a JH-response gene expressed in the seminal vesicle epithelium, suggesting insect seminal vesicles undergo metabolic regulation by JH. Together, this study sheds new light on the biology of the insect reproductive regulatory system. | Chien, C., He, K., Perry, S., Tchitchkan, E., Han, Y., Li, X., Dickman, D. (2025). Distinct input-specific mechanisms enable presynaptic homeostatic plasticity. Science advances, 11(7):eadr0262 PubMed ID: 39951523
Summary: Synapses are endowed with the flexibility to change through experience, but must be sufficiently stable to last a lifetime. This tension is illustrated at the Drosophila neuromuscular junction (NMJ), where two motor inputs that differ in structural and functional properties coinnervate most muscles to coordinate locomotion. To stabilize NMJ activity, motor neurons augment neurotransmitter release following diminished postsynaptic glutamate receptor functionality, termed presynaptic homeostatic potentiation (PHP). How these distinct inputs contribute to PHP plasticity remains enigmatic. This studied used a botulinum neurotoxin to selectively silence each input and resolve their roles in PHP, demonstrating that PHP is input specific: Chronic (genetic) PHP selectively targets the tonic MN-Ib, where active zone remodeling enhances Ca(2+) influx to promote increased glutamate release. In contrast, acute (pharmacological) PHP selectively increases vesicle pools to potentiate phasic MN-Is. Thus, distinct homeostatic modulations in active zone nanoarchitecture, vesicle pools, and Ca(2+) influx collaborate to enable input-specific PHP expression. |
Friday October 2nd - Disease Models |
| Koch, R., Nagoshi, E. (2025). Examining the potential involvement of NONO in TDP-43 proteinopathy in Drosophila. Eur J Neurosci, 61(1):e16632 PubMed ID: 39690447
Summary: The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), two ends of the same clinical, genetic, and pathological disease spectrum. TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. This study demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA), encoding a nuclear RNA-binding protein that regulates vision, courtship song production, circadian rhythms, and locomotor activity. Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms. | Gill, S., Mandigo, T. R., Elmali, A. D., Leger, B. S., ...., Saxena, R., Schreiber, S. L., Walker, J. A. (2024). A conserved role for ALG10/ALG10B and the N -glycosylation pathway in the sleep-epilepsy axis. medRxiv, PubMed ID: 39711723
Summary: Congenital disorders of glycosylation (CDG) comprise a class of inborn errors of metabolism resulting from pathogenic variants in genes coding for enzymes involved in the asparagine-linked glycosylation of proteins. Unexpectedly to date, no CDG has been described for ALG10, encoding the alpha-1,2-glucosyltransferase catalyzing the final step of lipid-linked oligosaccharide biosynthesis. Genome-wide association studies (GWAS) of human traits in the UK Biobank revealed significant SNP associations with short sleep duration, reduced napping frequency, later sleep timing and evening diurnal preference as well as cardiac traits at a genomic locus containing a pair of paralogous enzymes ALG10 and ALG10B. Modeling Alg10 loss in Drosophila, this study identified an essential role for the N -glycosylation pathway in maintaining appropriate neuronal firing activity, healthy sleep, preventing seizures, and cardiovascular homeostasis. This study further confirmed the broader relevance of neurological findings associated with Alg10 from humans and flies using zebrafish and nematodes and demonstrate conserved biochemical roles for N -glycosylation in Arabidopsis. A human subject is reported that was homozygous for variants in both ALG10 and ALG10B arising from a consanguineous marriage, with epilepsy, brain atrophy, and sleep abnormalities as predicted by the fly phenotype. Quantitative glycoproteomic analysis in the Drosophila model identifies potential key molecular targets for neurological symptoms of CDGs. |
| Mele, S., Martelli, F., Barlow, C. K., Jefferies, G., Dworkin, S., Christodoulou, J., Schittenhelm, R. B., Piper, M. D. W., Johnson, T. K. (2025). Valine Restriction Extends Survival in a Drosophila Model of Short-Chain Enoyl-CoA Hydratase 1 (ECHS1) Deficiency. J Inherit Metab Dis, 48(1):e12840 PubMed ID: 39727068
Summary: Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas the development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. This study reports on the establishment of a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including poor motor behaviour and early mortality and could be rescued by the expression of a human ECHS1 transgene. Both restriction of valine in isolation, or all branched-chain amino acids (BCAAs-leucine, isoleucine and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder. | Mishra, L., Mishra, M. (2024). Ribose-induced advanced glycation end products reduce the lifespan in Drosophila melanogaster by changing the redox state and down-regulating the Sirtuin genes. Biogerontology, 26(1):28 PubMed ID: 39702854
Summary: Advanced Glycation End (AGE) products are one such factor that accumulates during aging and age-related diseases. However, how exogenous AGE compounds cause aging is an area that needs to be explored. Specifically, how an organ undergoes aging and aging-related phenomena that need further investigation. The intestine is the most exposed area to food substances. How AGEs affect the intestine in terms of aging need to be explored. Drosophila melanogaster, a well-known model organism, is used to decode aging and age-associated phenomena. In this study, Ribose induced Advanced Glycation End products (Rib-AGE) fed to D. melanogaster was used to study the aging mechanism. The Rib-AGE-induced aging was checked in Drosophila. A series of changes was found in Rib-AGE-fed flies. Reactive oxygen species (ROS) and nitric oxide species (NOs) were higher in the Rib-AGE-fed flies, and the antioxidant level was lower. The intestinal permeability was altered. The microorganism load was higher inside the gut. The structural arrangement of the gut's microfilament was found to be damaged, and the nuclear shape was found to be irregular. Cell death within the gut was elevated in comparison to control. The food intake was found to be reduced. The relative mRNA expression of the histone deacetylases Sirtuin 2 and Sirtuin 6 gene of D. melanogaster was downregulated in Rib-AGE-fed flies compared to the control. All these findings strongly suggest that Rib-AGE accelerates aging and age-related disorders in D. melanogaster. |
| Bolshakova, O. I., Slobodina, A. D., Slepneva, E. E., Sarantseva, S. V. (2024). Acetyl-L-Carnitine Aids in Preservation of Cholinergic Neurons and Memory in the Drosophila melanogaster Model of Alzheimer's Disease. Curr Alzheimer Res, 21(8):557-565 PubMed ID: 39716786
Summary: The lack of effective therapy for the treatment of Alzheimer's disease demands both the search for new drugs and the reconsideration of already known substances currently used in other areas of medicine. Drosophila melanogaster offers the potential to model features of Alzheimer's disease, study disease mechanisms, and conduct drug screening. The purpose of this work was to analyze the neuroprotective properties of the drug "carnicetine", which is an acetylated form of the natural low molecular weight compound L-carnitine. The drug is able to cross the blood-brain barrier and is currently used as a means of improving cellular metabolism. Using tissue-specific drivers, direct expression of amyloid beta peptide (42 amino acids) was exhibited in certain groups of neurons in the Drosophila melanogaster brain, namely in dopaminergic and cholinergic neurons. The effect of acetyl-L-carnitine (carnicetine) on the death of these neurons and the memory of flies was analyzed. The expression of amyloid beta peptide in dopaminergic or cholinergic neurons resulted in neurodegeneration of cholinergic neurons in the Drosophila brain and memory impairment. The use of carnicetine added to animal food made it possible to treat these disorders. At the same time, no effect on dopaminergic neurons was noted. The data obtained confirmed the neuroprotective properties of the drug under study, demonstrating its participation in the restoration of the cholinergic system and the feasibility of using carnicetine for the treatment of Alzheimer's disease. | Gonskikh, Y., Tirrito, C., Bommisetti, P., Mendoza-Figueroa, M. S., Stoute, J., Kim, J., Wang, Q., Song, Y., Liu, K. F. (2025). Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function. Nucleic Acids Res, 53(2) PubMed ID: 39673800
Summary: Enzyme-mediated modifications of tRNA, such as 5-methylcytosine (m5C) installed by nuclear-enriched NOP2/Sun RNA methyltransferase 2 (NSUN2), play a critical role in neuronal development and function. However, understanding of these modifications' spatial installation and biological functions remains incomplete. This study demonstrates that a nucleoplasm-localized G679R NSUN2 mutant, linked to intellectual disability, diminishes NSUN2-mediated tRNA m5C in human cell lines and Drosophila. These findings indicate that inability of RNA methyltransferase G679R-NSUN2 to install m5C is primarily attributed to its reduced binding to tRNA rather than its nucleoplasmic localization. Conversely, an NSUN2 variant lacking an internal intrinsically disordered region (ΔIDR-NSUN2) can install ~80% m5C within the nucleoplasm. Furthermore, this study showed that tRNA m5C levels are positively correlated to cognitive performance in Drosophila, where expressing G679R-NSUN2 leads to the most severe social behavioral deficits while expressing ΔIDR-NSUN2 results in less pronounced deficits. This work illuminates the molecular mechanism underlying G679R disease mutation in cognitive function and offers valuable insights into the significance of the cellular localization of m5C installation on tRNA for neuronal function. |
Thursday, October 1st - Stress |
| Vrdoljak, J., Soto, I. M., Carreira, V. P., Padro, J. (2025). Environmental stress differentially affects phenotypic modularity and fluctuating asymmetry in generalist and specialist cactophilic Drosophila. Journal of evolutionary biology, 38(3):404-416 PubMed ID: 39821346
Summary: Modularity and developmental (in)stability have the potential to influence phenotype production and, consequently, the evolutionary trajectories of species. Depending on the environmental stress factors involved and the buffering capacity of an organism, different developmental outcomes are expected. Cactophilic Drosophila species provide an established eco-evolutionary model with well-studied ecological conditions, making them ideal for studying these phenomena. This study investigated how variations in larval diet and exposure to alkaloids on primary and secondary host plants affect the degree of integration/modularity and fluctuating asymmetry (FA, a proxy for developmental instability) of wing shape in two sibling species with different degrees of specialisation: Drosophila buzzatii (generalist) and Drosophila koepferae (specialist). Additionally, the anterior-posterior modular configuration was compared with a recently proposed proximal-distal modular configuration. The results revealed greater independence among proximal-distal modules compared to anterior-posterior modules. Moreover, sex-specific responses were observed, with males exhibiting greater susceptibility to stressful environments than females. Each species showed a particular trait pattern across treatments: D. buzzatii showed increased integration and FA when reared in a nutrient-poor, alkaloid-rich secondary host, while D. koepferae displayed similar responses in novel environments characterised by double doses of alkaloids on the secondary host plant. These findings align with the generalist-specialist paradigm, suggesting that specialists may be challenged by novel environments, whereas generalists may be more affected by stressful conditions. This study highlights the importance of considering each part of the proximal-distal wing axis independently, and the need to consider ecological-evolutionary history when investigating the relationship between complex phenotypic traits and environmental stress. | Shields, S., Gregory, E., Wilkes, O., Gozes, I., Sanchez-Soriano, N. (2025). Oxidative Stress Promotes Axonal Atrophy through Alterations in Microtubules and EB1 Function. Aging Dis, PubMed ID: 39908272
Summary: Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence, aged axons are more susceptible to damage or dysfunction. Understanding how aging causes axonal vulnerability is crucial for developing strategies to enhance overall resilience of neurons and prevent neuronal deterioration during aging and in age-related neurodegenerative diseases. Increasing levels of reactive oxygen species (ROS) causes oxidative stress - a hallmark of aging and age-related diseases. Despite this association, a causal relationship between oxidative stress and neuronal aging remains unclear, particularly in how subcellular physiology may be affected by ROS. By using Drosophila-derived primary neuronal cultures and a recently developed in vivo neuronal model of aging, which involves the visualisation of Drosophila medulla neurons, this study investigated the interplay between oxidative stress, neuronal aging and the microtubule cytoskeleton. The results showed that oxidative stress is a key driver of axonal and synaptic decay, as shown by an enhanced appearance of axonal swellings, microtubule alterations (in both axons and synapses) and morphological transformation of axonal terminals during aging. Increasing the levels of ROS sensitises microtubule plus end-binding protein 1 (EB1), leading to microtubule defects that effect neuronal integrity. Furthermore, manipulating EB1 proved to be a valuable therapeutic strategy to prevent aging hallmarks enhanced in conditions of elevated ROS. In summary, a mechanistic pathway linking cellular oxidative stress with changes in the microtubule cytoskeleton leading to axonal deterioration during aging was demonstrated and evidence was provided of the therapeutic potential of enhancing microtubule plus-end physiology to improve the resilience of axons. |
| Hunter-Manseau, F., Cormier, J., Pichaud, N. (2025). From molecular to physiological responses: improved stress tolerance and longevity in Drosophila melanogaster under fluctuating thermal regimes. J Exp Biol, 228(2) PubMed ID: 39698946
Summary: Climate change introduces greater thermal variability, profoundly affecting ectothermic species whose body temperatures rely heavily on the environment. Understanding the physiological and metabolic responses to such variability is crucial for predicting how these species will cope with changing climates. This study investigates how chronic thermal stress impacts mitochondrial metabolism and physiological parameters in Drosophila melanogaster, hypothesizing that a fluctuating thermal regime (FTR) activates protective mechanisms enhancing stress tolerance and longevity. To test this, Drosophila were exposed to constant 24°C or to an FTR of 24°C:15°C (day:night) cycle following an initial 5 day period at 24°C. The FTR group exhibited rapid transcript level changes after the first day of FTR, particularly those related to heat shock proteins, mitophagy and regulatory factors, which returned to initial levels after 5 days. Mitochondrial respiration rates initially decreased after 1 and 2 days of FTR, then recovered by day 5, indicating rapid acclimation. Enhanced antioxidant enzyme activities were observed early in the FTR group, after 1 day for mtSOD and SODcyt+ext and 3 days for both SOD and catalase, followed by a decline by day 5, suggesting efficient oxidative stress management. The FTR group showed lower CTmax on day 3, reflecting possible physiological strain at that time point, and complete recovery by day 5. Longevity increased under FTR, highlighting the activation of protective mechanisms with beneficial long-term effects. These results suggest that FTR prompts a temporal succession of rapid physiological adjustments at different levels of organisation, enhancing long-term survival in D. melanogaster. | Dhadde, S. B., Kalshetti, M. S. (2025). Chromium-histidine complex enhances reproductive physiology and development in Drosophila melanogaster by modulating oxidative stress. Biometals, 38(1):321-335 PubMed ID: 39680280
Summary: The interaction of metal ions with biological systems plays a critical role in cellular functions, including oxidative stress regulation and metabolic health. This study aimed to explore the effects of the chromium-histidine complex [Cr(hist)(3)] on reproductive success, developmental processes, and oxidative stress defence in Drosophila melanogaster. Wild-type D. melanogaster flies were exposed to Cr(hist)(3) at concentrations of 5, 10, 15, and 20 μg/ml, and physiological parameters-including fecundity, fertility, developmental timelines, and antioxidant enzyme activity-were measured. The results indicate that Cr(hist)(3) at 15 μg/ml optimally enhanced reproductive health and developmental efficiency. Specifically, fecundity and fertility increased by 15.6% and 15.5%, respectively, and egg-to-adult viability improved by 15.6% compared to controls. Developmental timelines were shortened, with larval and pupal periods reduced by 7.6% and 7.1%. Additionally, Cr(hist)(3) treatment led to a significant downregulation of lipid peroxidation (MDA) by 17.54% and upregulation in antioxidant enzymes (catalase, glutathione-S-transferase, and superoxide dismutase), indicating improved cellular defence against oxidative damage. Flies treated with 15 μg/ml Cr(hist)(3)(3) also exhibited a 9.7% increase in lifespan. These findings suggest that Cr(hist)(3) enhances reproductive success and developmental dynamics through oxidative stress regulation, highlighting its potential for applications in insect health and stress management. This study contributes to the understanding of metal ion interactions in biological systems and their physiological effects. |
| Shekhar, S., Tracy, C., Lidsky, P. V., Andino, R., Wert, K. J., Kramer, H. (2025). Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors. Nature communications, 16(1):252 PubMed ID: 39747204
Summary: Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, this study observed non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain. | Romano, N. C, Marchetti, M., Marangoni, A., Leo, L., Retrosi, D., Rosato, E., Fanti, L. (2024). Neuronal Progenitors Suffer Genotoxic Stress in the Drosophila Clock Mutant per(0). Cells, 13(23) PubMed ID: 39682693
Summary: The physiological role and the molecular architecture of the circadian clock in fully developed organisms are well established. Yet, there is limited understanding of the function of the clock during ontogenesis. This study used a null mutant (per0) of the clock gene period (per) in Drosophila melanogaster to ask whether PER may play a role during normal brain development. In third-instar larvae, per resulted in increased genotoxic stress compared to wild-type controls. Increased double-strand DNA breaks in the central nervous system and chromosome aberrations were detected in dividing neuronal precursor cells. Reactive oxygen species (ROS) are causal to the genotoxic effect, and expression of PER in glia is necessary and sufficient to suppress such a phenotype. Finally, the absence of PER may result in less condensed chromatin, which contributes to DNA damage. |
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