What's hot today: Current papers in developmental biology and gene function

What's hot today:
Current papers in developmental biology and gene function

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Wednesday January 28th, 2026 - Behavior

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Huang, Y. C., Costa, C. A. M., Ruiz, N. V., Wang, X., Jevitt, A., Breneman, C. M., Han, C., Deng, W. M. (2025). Polyploidy promotes transformation of epithelial cells into non-professional phagocytes. bioRxiv, PubMed ID: 40196694
Summary:
Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, non-professional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell-derived NPPs during oogenesis in Drosophila. This study reports that the transformation of follicle cells into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). It was further shown that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of follicle cells into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, polyploidy in epidermal cells, another type of NPPs, is shown to be important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions.

Singh, J., Verma, D., Sarkar, B., Paul, M. S., Mutsuddi, M., Mukherjee, A. (2025). Notch and LIM-homeodomain protein Arrowhead regulate each other in a feedback mechanism to play a role in wing and neuronal development in Drosophila. Open Biol, 15(4):240247 PubMed ID: 40300650
Summary:
The Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. To identify novel effectors of Notch signalling, this study analysed the whole transcriptome of Drosophila wing and eye imaginal discs in which an activated form of Notch was overexpressed. A LIM-homeodomain protein, Arrowhead (Awh), was identified as a novel candidate that plays a crucial role in Notch-mediated developmental events. Awh alleles show strong genetic interaction with Notch pathway components. Awh loss-of-function upregulates Notch targets Cut and Wingless. Awh gain-of-function downregulates Notch targets by reducing the expression of the ligand Delta. Consequently, the expression of the Wingless effector molecule Armadillo and its downstream targets, Senseless and Vestigial, also gets downregulated. Awh overexpression leads to ectopic expression of engrailed, a segment polarity gene in the anterior region of wing disc, leading to patterning cdefects. Additionally, Notch gain-of-function-mediated neuronal defects get significantly rescued with Awh overexpression. Activated Notch inhibits Awh activity, suggesting a regulatory loop between Awh and Notch. Additionally, the defects caused by Awh gain-of-function were remarkably rescued by Chip, a LIM interaction domain containing transcriptional co-factor. The present study highlights the novel feedback regulation between Awh and Notch.

Fujinaga, D., Nolan, C., Yamanaka, N. (2025). Functional characterization of eicosanoid signaling in Drosophila development. PLoS Genet, 21(5):e1011705 PubMed ID: 40344083
Summary:
20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have not been thoroughly investigated. Phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, the Drosophila genome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 in Drosophila S2 cells. PGR mutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen. Consistent with this, through a comprehensive mutagenesis approach, this study identified a Drosophila PGE synthase whose mutants show similar pharate adult lethality with hypoxia responses. Drosophila thus has a highly simplified eicosanoid signaling pathway as compared to humans, and it may provide an ideal model system for investigating evolutionarily conserved aspects of eicosanoid signaling.

Zhao, Y., Alexandre, C., Kelly, G., Vincent, J. P., Perez-Mockus, G. (2025). HIF-1alpha-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development. Nat Commun, PubMed ID: 41423448
Summary:
Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1alpha stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. This study confirm the expectation that rising levels of HIF-1alpha dampen TOR signalling activity through transcriptional activation of REDD1 (Scylla and Charybdis) . Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1alpha levels and activity. Thus, HIF-1alpha mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1alpha knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. It is concluded that Sima/HIF-1alpha prevents TOR-mediated growth from depleting local oxygen supplies during normal development.

Medina, A. B., Perochon, J., Tian, Y., Johnson, C. T., Holcombe, J., Ramesh, P., Polcownuk, S., Yu, Y., Cordero, J. B. (2025). Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila. Dev Cell, 60(22):3085-3101 e3086 PubMed ID: 40695286
Summary:
Robust and controlled intestinal regeneration involves reciprocal interactions between the intestinal epithelium and its microenvironment. This study identifed signaling between enteroendocrine (EE) cells, vasculature-like trachea, and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Reactive oxygen species (ROS) from midgut cells promote production and secretion of diuretic hormone 31 (Dh31), from anterior midgut enteroendocrine (EE) cells. EE and neuronal Dh31 activate tracheal Dh31 receptor, leading to the production of the vascular endothelial growth factor (VEGF)- and platelet-derived-growth-factor (PDGF)-like ligand Pvf1. Pvf1 induces tracheal remodeling and intestinal stem cell (ISC) proliferation through autocrine and paracrine Pvr/mitogen-activated protein kinase (MAPK) signaling, respectively. While EE Dh31 exerts broad control of ISC proliferation throughout the midgut, effects of the neuronal source of the ligand appear restricted to the posterior midgut. Collectively,this work discovered an EE/neuronal/vascular signaling network, controlling global and domain-specific ISC proliferation during adult intestinal regeneration.

Ahrentlov, N., Kubrak, O., Lassen, M., Malita, A., Koyama, T., Frederiksen, A. S., Sigvardsen, C. M., John, A., Madsen, P. E. H., Halberg, K. V., Nagy, S., Imig, C., Richter, E. A., Texada, M. J., Rewitz, K. (2025). Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan. Nat Metab, 7(6):1223-1245 PubMed ID: 40229448
Summary:
Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. This study identified tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, this study delineated a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. These results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.

Wednesday January 21st - Transcriptional Regulation

Chen, X., Yan, X., Jing, C., Fu, B., Jin, W., Zhang, S., Wang, M., Liu, F., Sun, L. (2025). Ginsenoside Rc maintains sleep rhythm homeostasis by alleviating oxidative stress. Phytomedicine, 141:156634 PubMed ID: 40203472
Summary:
Sleep disorders significantly impact physical health and quality of life. However, the current treatment strategies have several limitations. Panax ginseng (known as Asian ginseng, Korean ginseng, or Chinese ginseng) has been traditionally employed to calm the mind, but its active components and their mechanisms remain elusive. This study aimed to elucidate the sleep-improving actions of Panax ginseng active component, ginseng Rc, and its potential mechanisms. Sleep duration and rhythm of Drosophila were assessed via a behavior analysis system. Furthermore, the potential addictive side effects of ginsenoside Rc were assessed through capillary ingestion. Changes in mRNA levels of core clock genes and stress response-related genes were determined via RT-qPCR. In addition, the potential mechanisms underlying the efficacy of ginsenoside Rc were evaluated by transcriptomic methodologies. A molecular operating environment (MOE)-Dock simulation was conducted to predict the binding affinity between Pink1 and ginsenoside Rc and verified by surface plasmon resonance. Lastly, Western blotting was carried out to assess Sir2 expression and acetylation of brain proteins. It was observed that ginsenoside Rc improved sleep duration, latency, fragmentation, and amplitude. Furthermore, it upregulated the expression of the clock gene and was not addictive or dependency-inducing. Moreover, it increased antioxidant-related gene expression and reduced stress-related gene expression. In addition, transcriptomic analysis demonstrated that ginsenoside Rc also upregulated autophagy-related genes. Mechanistic studies showed that it improves sleep homeostasis by activating the Pink1/Sir2 signaling pathway, reducing oxidative stress, and modulating protein acetylation levels. This study identified ginsenoside Rc, a novel compound from ginseng, and revealed that it can maintain sleep homeostasis. Mechanistically, ginsenoside Rc alleviated oxidative stress by targeting Pink1 and Sir2. These findings provide evidence for the potential clinical application of ginsenoside Rc for treating sleep disorders.

Iwasaki, K., Neuhauser, C., Stokes, C., Rayshubskiy, A. (2025). The fruit fly, Drosophila melanogaster, as a microrobotics platform. Proc Natl Acad Sci U S A, 122(15):e2426180122 PubMed ID: 40198707
Summary:
Engineering small autonomous agents capable of operating in the microscale environment remains a key challenge, with current systems still evolving. This study explores the fruit fly, Drosophila melanogaster, a classic model system in biology and a species adept at microscale interaction, as a biological platform for microrobotics. Initially, this study focuses on remotely directing the walking paths of fruit flies in an experimental arena. This was acclompished through two distinct approaches: harnessing the fruit flies' optomotor response and optogenetic modulation of its olfactory system. These techniques facilitate reliable and repeated guidance of flies between arbitrary spatial locations. Flies were guided along predetermined trajectories, enabling them to scribe patterns resembling textual characters through their locomotion. Olfactory-guided navigation was enhanced through additional optogenetic activation of attraction-inducing mushroom body output neurons. This control was extended to collective behaviors in shared spaces and navigation through constrained maze-like environments. The guidance technique was furher used to enable flies to carry a load across designated points in space, establishing the upper bound on their weight-carrying capabilities. Additionally, it was demonstrated that visual guidance can facilitate novel interactions between flies and objects, showing that flies can consistently relocate a small spherical object over significant distances. Last, it was demonstrated multiagent formation control, with flies alternating between distinct spatial patterns. Beyond expanding tools available for microrobotics, these behavioral contexts can provide insights into the neurological basis of behavior in fruit flies.

Deal, S. L., Bei, D., Gibson, S. B., Delgado-Seo, H., Fujita, Y., Wilwayco, K., Seto, E. S., Yamamoto, S. (2025). RNAi-based screen for pigmentation in Drosophila melanogaster reveals regulators of brain dopamine and sleep. bioRxiv, PubMed ID: 40236063
Summary:
The dopaminergic system has been extensively studied for its role in behavior in animals as well as human neuropsychiatric and neurological diseases. However, little is known about how dopamine levels are tightly regulated in vivo. To identify novel regulators of dopamine, Drosophila melanogaster cuticle pigmentation was used as a readout, where dopamine is a precursor to melanin. We measured dopamine from genes known to be critical for cuticle pigmentation and performed an RNAi-based screen to identify new regulators of pigmentation. 153 potential pigmentation genes were found that were enriched for conserved homologs and disease- associated genes as well as developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 10 were fpimd to cause significant reduction in head dopamine levels and one caused an increase. Two genes, clueless and mask (multiple ankyrin repeats single KH domain), upon knockdown, reduced dopamine levels in the brain. Further examination suggests that Mask regulates the transcription of the rate-limiting dopamine synthesis enzyme, tyrosine hydroxylase, and its knockdown causes dopamine-dependent sleep phenotypes. In summary, by studying genes that affect cuticle pigmentation, a phenotype seemingly unrelated to the nervous system, it was possible to identify several genes that affect dopamine metabolism as well as a novel regulator of behavior.

Benoit, J. B., Bose, J., Ajayi, O. M., Webster, A., Grieshop, K., Lewis, D., Talbott, H., Polak, M. (2025). Shifted levels of sleep and activity during the night as mechanisms underlying ectoparasite resistance. NPJ Biol Timing Sleep, 2(1):15 PubMed ID: 40191448
Summary:
Parasites harm host fitness and are pervasive agents of natural selection capable of driving the evolution of host resistance traits. previous work demonstrated evolutionary responses to artificial selection for increasing behavioral immunity to Gamasodes queenslandicus mites for Drosophila melanogaster. This study reports transcriptional shifts in metabolic processes due to selection for mite resistance. Dcreased starvation resistance and increased use of nutrient reserves in flies from mite-resistant lines were demonstrated. Resistant lines exhibited increased activity, reduced sleep, and elevated oxygen consumption during the night. Using a panel of D. melanogaster lines exhibiting variable sleep durations, a positive correlation was found between mite resistance and reduced sleep. Restraining the activity of artificially selected mite-resistant flies during exposure to parasites reduced their resistance advantage relative to control flies. The results suggest that ectoparasite resistance in this system involves increased activity during the scotophase (the dark portion of a photoperiod cycle) and metabolic gene expression at the expense of starvation resistance.

Cui, T., Wang, T. (2025). Exact box-counting and temporal sampling algorithms for fractal dimension estimation with applications to animal behavior analysis. Results Eng, 25 PubMed ID: 40230598
Summary:
Fractal dimension (FD) is a widely recognized metric in mathematics and physics for quantifying the complexity of intricate objects and processes. Tis study proposes novel algorithms to estimate the FD of animal movement using high-resolution spatial and temporal data. To enhance estimation accuracy, an oversampling technique was developed that linearly interpolates between adjacent points on movement paths. Furthermore, an exact box-counting algorithm was introduced, tailored for piecewise linear paths, ensuring accurate fractal dimension estimations. Considering that animal behavior is typically recorded at fixed frame rates, a temporal sampling method was also proposed for calculating FD using temporal domain scales. Recognizing that FD varies with scale, a dual total least squares method was employed to identify the optimal scale for FD comparisons across different genotypes. Through large-scale experiments on the movement of Drosophila melanogaster larvae, mutations were showed in the schizophrenia-associated gene Dysbindin significantly increase FD, suggesting potential impairments in motor function. These findings highlight FD as a robust and quantitative metric for assessing the complexity of movement behavior.

Bath, E., Gleason, J. (2025). Is variation in female aggressiveness across Drosophila species associated with reproductive potential?. Proc Biol Sci, 292(2044):20242301 PubMed ID: 40199353
Summary:
Aggression is a key determinant of fitness in many species, mediating access to mates, food and breeding sites. Variation in intrasexual aggression across species is likely to be driven by variation in resource availability and distribution. While males primarily compete over access to mates, females are likely to compete over resources to maximize offspring quantity and/or quality, such as food or breeding sites. To date, however, most studies have focused on male aggression, and little is known about drivers of female aggression across species. To investigate potential reproductive drivers of female aggression, the relationship between three reproductive traits and aggression was tested in eight Drosophila species. Using machine learning classifiers developed for Drosophila melanogaster, aggressive behaviours displayed in the presence of yeast for mated and unmated females. Female aggression was correlated with ovariole number across species, suggesting that females who lay more eggs are more aggressive. A need for resources for egg production or oviposition sites may therefore be drivers of female aggression, though other potential hypotheses are discussed.

Tuesday January 17th - Evolution

Lai, W. Y., Hsu, S. K., Futschik, A., Schlotterer, C. (2025). Pleiotropy increases parallel selection signatures during adaptation from standing genetic variation. Elife, 13 PubMed ID: 40227842
Summary:
The phenomenon of parallel evolution, whereby similar genomic and phenotypic changes occur across replicated pairs of populations or species, is widely studied. Nevertheless, the determining factors of parallel evolution remain poorly understood. Theoretical studies have proposed that pleiotropy, the influence of a single gene on multiple traits, is an important factor. In order to gain a deeper insight into the role of pleiotropy for parallel evolution from standing genetic variation, this study characterized the interplay between parallelism, polymorphism, and pleiotropy. The present study examined the parallel gene expression evolution in 10 replicated populations of Drosophila simulans, which were adapted from standing variation to the same new temperature regime. The data demonstrate that the parallel evolution of gene expression from standing genetic variation is positively correlated with the strength of pleiotropic effects. The ancestral variation in gene expression is, however, negatively correlated with parallelism. Given that pleiotropy is also negatively correlated with gene expression variation, a causal analysis was conducted to distinguish cause and correlation and evaluate the role of pleiotropy (a genetic phenomenon where a single gene influences multiple, seemingly unrelated phenotypic traits, often because the gene's product is used in various cells or pathwaysa genetic phenomenon where a single gene influences multiple, seemingly unrelated phenotypic traits, often because the gene's product is used in various cells or pathways). The causal analysis indicated that both direct (causative) and indirect (correlational) effects of pleiotropy contribute to parallel evolution. The indirect effect is mediated by historic selective constraint in response to pleiotropy. This results in parallel selection responses due to the reduced standing variation of pleiotropic genes. The direct effect of pleiotropy is likely to reflect a genetic correlation among adaptive traits, which in turn gives rise to synergistic effects and higher parallelism.

Glaser-Schmitt, A., Lebherz, M., Saydam, E., Bornberg-Bauer, E., Parsch, J. (2025). Expression of De Novo Open Reading Frames in Natural Populations of Drosophila melanogaster. J Exp Zool B Mol Dev Evol, PubMed ID: 40231390
Summary:
De novo genes, which originate from noncoding DNA, are known to have a high rate of turnover over short evolutionary timescales, such as within a species. Thus, their expression is often lineage- or genetic background-specific. However, little is known about their levels and breadth of expression as populations of a species diverge. This study utilized publicly available RNA-seq data to examine the expression of newly evolved open reading frames (neORFs) in comparison to non- and protein-coding genes in Drosophila melanogaster populations from the derived species range in Europe and the ancestral range in sub-Saharan Africa. These datasets included two adult tissue types as well as whole bodies at two temperatures for both sexes and three larval/prepupal developmental stages in a single tissue and sex, which allowed examining neORF expression and divergence across multiple sample types as well as sex and population. A relatively large proportion (approximately 50%) was detected of annotated neORFs as expressed in the population samples, with neORFs often showing greater expression divergence between populations than non- or protein-coding genes. However, differential expression of neORFs between populations tended to occur in a sample type-specific manner. On the other hand, neORFs displayed less sex-biased expression than the other two gene classes, with the majority of sex-biased neORFs detected in whole bodies, which may be attributable to the presence of the gonads. neORFs were found to be shared among multiple lines in the original set of inbred lines in which they were first detected were more likely to be both expressed and differentially expressed in the new population samples, suggesting that neORFs at a higher frequency (i.e. present in more individuals) within a species are more likely to be functional.

Blair, L. K., Cridland, J. M., Luo, Y., Begun, D. J., Kopp, A. (2025). Improved sampling of genotypes and species reveals new insights on de novo gene history and regulatory origins. Genetics, 230(2) PubMed ID: 40250972
Summary:
The evolution of genes de novo from ancestrally nongenic sequences may be a significant mechanism of gene origin. Many studies have focused on identifying de novo genes in distant evolutionary comparisons, which bias the sample of de novo genes toward older genes that have acquired important functions and have been retained and refined by selection. This report focuses on the earliest steps in de novo gene origin by identifying young, polymorphic transcripts that may be missed by other study designs. To accomplish this, we sequenced tissue transcriptomes from a much larger sample of genotypes than have been used in previous analyses of de novo genes in Drosophila melanogaster. 90 potential species-specific de novo genes were identified expressed in the male accessory glands of 29 D. melanogaster lines derived from the same natural population. Most young transcripts were found to be both rare in the population and transcribed at low abundance. Improved sampling of both ingroup and outgroup genotypes reveals that many young genes are polymorphic in more than 1 species, resulting in substantial uncertainty about the age and phylogenetic distribution of de novo genes. Among the genes expressed in the same tissue, gene age correlates with proximity to other tissue-specific genes, with the youngest genes being least likely to occur near established tissue-specific genes. This and other lines of evidence suggest that de novo genes do not commonly evolve by simply reutilizing preexisting regulatory elements. Together, these results provide new insights into the origin and early evolution of de novo genes.

Hey, J., Pavinato, V. A. C. (2025). Isolating selective from non-selective forces using site frequency ratios. PLoS Genet, 21(4):e1011427 PubMed ID: 40258089
Summary:
A new method is introduced for estimating the distribution of mutation fitness effects using site frequency spectra. Unlike previous methods, which make assumptions about non-selective factors, or that try to incorporate such factors into the underlying model, this new method mostly avoids non-selective effects by working with the ratios of counts of selected sites to neutral sites. An expression for the likelihood of a set of selected/neutral ratios is found by treating the ratio of two Poisson random variables as the ratio of two gaussian random variables. This approach also avoids the need to estimate the relative mutation rates of selected and neutral sites. Simulations over a wide range of demographic models, with linked selection effects show that the new SFRatios method (a behavioral technique used to quantify food intake by measuring the feeding frequency [proboscis-extension) of flies], performs well for statistical tests of selection, and it performs well for estimating the distribution of selection effects. Performance was better with weak selection models and for expansion and structured demographic models than for bottleneck models. Applications to two populations of Drosophila melanogaster reveal clear but very weak selection on synonymous sites. For nonsynonymous sites, selection was found to be consistent with previous estimates and stronger for an African population than for one from North Carolina.

Audet, T., Wilson, A., Dukas, R., Dworkin, I. (2025). The role of resource defensibility in facilitating sexually-selected weapon evolution: An experimental evolution test. Evolution, PubMed ID: 40201973
Summary:

Animal weapons have evolved multiple times primarily for battling for access to mates. Despite intra-sexual selection being common, exaggerated weapons have evolved relatively rarely. So why do exaggerated weapons not evolve more commonly? It has been hypothesized that three conditions are necessary for evolution of exaggerated weapons: high variance in reproductive success, patchy, high-value resources, and spatial environments conducive to one-on-one competition. Here, we test this hypothesis by performing experimental evolution in Drosophila melanogaster, utilizing heterogeneous environments where conditions facilitating territorial defense and opportunities for competitive interactions vary. We examine changes in sexually dimorphic morphology and male aggression that are predicted to occur, based on this model. Whether condition dependence for sexual dimorphism has evolved after 35 and 75 generations of experimental evolution was studied. Aggression did increase, albeit modestly, in environments that facilitate resource defense. Morphological changes are modest although with some trait specific changes to allometry, generally in the opposite direction of this study's predictions. Condition dependence trends in the opposite direction from those predicted by the hypothesis as well. The results are discussed in the context of the necessary conditions for the evolution of exaggerated weapons, and if, and when condition dependence may evolve.

Arnce, L. R., Bubnell, J. E., Aquadro, C. F. (2025). Comparative Analysis of Drosophila Bam and Bgcn Sequences and Predicted Protein Structural Evolution. J Mol Evol, 93(2):278-291 PubMed ID: 40178596
Summary:
The protein encoded by the Drosophila melanogaster gene bag of marbles (bam) plays an essential role in early gametogenesis by complexing with the gene product of benign gonial cell neoplasm (bgcn) to promote germline stem cell daughter differentiation in males and females. This study compared the AlphaFold2 and AlphaFold Multimer predicted structures of Bam protein and the Bam:Bgcn protein complex between D. melanogaster, D. simulans, and D. yakuba, where bam is necessary in gametogenesis to that in D. teissieri, where it is not. Despite significant sequence divergence, very little evidence was found of significant structural differences in high confidence regions of the structures across the four species. This suggests that Bam structure is unlikely to be a direct cause of its functional differences between species and that Bam may simply not be integrated in an essential manner for GSC differentiation in D. teissieri. Patterns of positive selection and significant amino acid diversification across species is consistent with the Selection, Pleiotropy, and Compensation (SPC) model, where detected selection at bam is consistent with adaptive change in one major trait followed by positively selected compensatory changes for pleiotropic effects (in this case perhaps preserving structure). In the case of bam, The major trait could be genetic interaction with the endosymbiotic bacteria Wolbachia pipientis. Following up on detected signals of positive selection and comparative structural analysis could provide insight into the distribution of a primary adaptive change versus compensatory changes following a primary change.

Thursday, January 15th - Disease Models

Wednesday January 21st - Transcriptional Regulation

Evdokimova, A. A., Kolesnikova, T. D., Mazina, M. Y., Krasnov, A. N., Erokhin, M., Chetverina, D., Vorobyeva, N. E. (2025). Transcriptional induction by ecdysone in Drosophila salivary glands involves an increase in chromatin accessibility and acetylation. Nucleic Acids Res, 53(7) PubMed ID: 40239993
Summary:
Transcriptional activation by 20-hydroxyecdysone (20E) in Drosophila provides an excellent model for studying tissue-specific responses to steroids. An increase in the 20E concentration regulates the degradation of larval and the proliferation of adult tissues during metamorphosis. To study 20E-dependent transcription, the natural system was used for controlling the 20E concentration-the E23 membrane transporter- which exports 20E from the cell. E23 was artificially expressed in tissues to suppress the first wave of 20E-inducible transcription at metamorphosis. E23 expression revealed a plethora of 20E-dependent genes in alivary glands, while mildly affecting transcription in brain. The mechanisms are described controlling transcriptional activation by 20E in salivary glands. 20E depletion decreased the binding of Pol II and the TFIID subunit, TBP, to the promoters of primary targets, demonstrating the role of 20E in transcription initiation. At target loci, 20E depletion resulted in the malfunctioning of sites co-bound with EcR and CBP/Nejire and enriched for the mark inherent to active enhancers. At these sites, the 20E concentration was found to control chromatin accessibility and acetylation. It is suggested that the activity of these 'active' ecdysone-sensitive elements was responsible for the active status of 20E targets in the salivary glands of wandering larvae.

Dahn, S., Wagner, A. E. (2025). Drosophila melanogaster as a model organism to investigate sex specific differences. Sci Rep, 15(1):19648 PubMed ID: 40467909
Summary:
Sex differences in physiology, anatomy, behavior, and genetics are well-documented throughout the animal kingdom. These differences are often neglected in research. This imbalance can have detrimental effects, as seen in cases where certain drugs have stronger side effects in females than in males. The fruit fly, Drosophila melanogaster, presents a promising model for studying these sex-specific differences because it shares many disease-related genes and is easy to use. RNA of 10-day-old and 30-day-old D. melanogaster (w¹¹¹⁸) was isolated and sequenced. In 10-day-old flies 3969 genes are significantly higher expressed in males than in females, and 7176 genes are significantly lower expressed in males. In 30-day-old males 3735 genes are significantly higher expressed than in females, and 7101 genes are significantly lower expressed. In detail, the present study shows that male flies exhibit higher expression levels of genes involved in toll signaling, Imd signaling, insulin signaling, and lipid metabolism. These findings highlight D. melanogaster as a valuable model organism for studying sex differences in these highly conserved signaling pathways. This model could help analyzing the sex-specific effects of dietary interventions or drugs, ultimately leading to a better understanding of sex-specific interconnections and improving the development of more effective, sex-specific medical treatments.

Sun, Y., Shui, K., Li, Q., Liu, C., Jin, W., Ni, J. Q., Lu, J., Zhang, L. (2025). Upstream open reading frames dynamically modulate CLOCK protein translation to regulate circadian rhythms and sleep. PLoS Biol, 23(5):e3003173 PubMed ID: 40354412
Summary:
The circadian rhythm is an evolutionarily conserved mechanism with translational regulation increasingly recognized as pivotal in its modulation. This study found that upstream open reading frames (uORFs) are enriched in Drosophila circadian rhythm genes, with particularly conserved uORFs present in core circadian clock genes. Evidence is presented that the uORFs of the core clock gene, Clock (Clk), rhythmically and substantially attenuate CLK protein translation in Drosophila, with pronounced suppression occurring during daylight hours. Eliminating Clk uORFs leads to increased CLK protein levels during the day and results in a shortened circadian cycle, along with a broad shift in clock gene expression rhythms. Notably, Clk uORF deletion also augments morning sleep by reducing dopaminergic activity. Beyond daily circadian adjustments, Clk uORFs play a role in modulating sleep patterns in response to seasonal daylight variations. Furthermore, the Cl uORFs act as an important regulator to shape the rhythmic expression of a vast array of genes and influence multifaceted physiological outcomes. Collectively, this research sheds light on the intricate ways uORFs dynamically adjust downstream coding sequences to acclimate to environmental shifts.

Fallacaro, S., Mukherjee, A., Turner, M. A., Garcia, H. G., Mir, M. (2025). Transcription factor hubs exhibit gene-specific properties that tune expression. bioRxiv, PubMed ID: 40291650
Summary:
The spatial and temporal control of gene expression relies on transcription factors binding to and occupying their target sites. Transcription factor hubs-localized, high-concentration microenvironments-promote transcription by facilitating binding and recruitment of transcriptional machinery and co-factors. Hubs are often thought to have emergent nucleus-wide properties depending on transcription factor nuclear concentrations and intrinsic, protein sequence-dependent properties. This global model does not account for gene-specific hub regulation. Using high-resolution lattice light-sheet microscopy in Drosophila embryos, hubs formed by the morphogen transcription factor, Dorsal, was examined at reporter genes with distinct enhancer compositions. snail was found to recruit long-lived, high-intensity hubs; sog exhibits shorter-lived, lower-intensity hubs; and hunchback, lacking Dorsal binding sites, shows only transient hub interactions. Hub intensity and interaction duration correlate with burst amplitude, RNAPII loading rate, and transcriptional output. These findings challenge the global view of hub formation and support a model where hub properties are locally tuned in a gene-specific manner to regulate transcriptional kinetics.

Kemp, J. P., Jr., Geisler, M. S., Hoover, M., Cho, C. Y., O'Farrell, P. H., Marzluff, W. F., Duronio, R. J. (2025). Cell-cycle-regulated transcriptional pausing of Drosophila replication-dependent histone genes. Mol Biol Cell, 36(7):ar88 PubMed ID: 40397569
Summary:
Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S-phase, but the molecular steps in transcription that are cell-cycle regulated are unknown. We report that Drosophila RNA Pol II promotes HLB formation and is enriched in the HLB outside of S-phase, including G(1)-arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S-phase. Proliferating cells in the wing and eye primordium express full-length histone mRNAs during S-phase but express only short nascent transcripts in cells in G(1) or G(2) consistent with these transcripts being paused and then terminated. Full-length transcripts are produced when Cyclin E/Cdk2 is activated as cells enter S-phase. Thus, activation of transcription elongation by Cyclin E/Cdk2 and not recruitment of RNA pol II to the HLB is the critical step that links histone gene expression to cell-cycle progression.

Chatsirisupachai, K., Moene, C. J. I., Kleinendorst, R., Kreibich, E., Molina, N., Krebs, A. (2025). Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II. Mol Syst Biol, 21(5):447-471 PubMed ID: 40164797
Summary:
The general transcription machinery and its occupancy at promoters are highly conserved across metazoans. This contrasts with the kinetics of mRNA production that considerably differ between model species such as Drosophila and mouse. The molecular basis for these kinetic differences is currently unknown. This study used Single-Molecule Footprinting to measure RNA Polymerase II (Pol II) occupancy, the fraction of DNA molecules bound, at promoters in mouse and Drosophila cell lines. Single-molecule data reveals that Pol II occupancy is on average 3-5 times more frequent at transcriptionally active Drosophila promoters than active mouse promoters. Kinetic modelling of the occupancy states suggests that these differences in Pol II occupancy are determined by the ratio between the transcription initiation and Pol II turnover rates. Chemical perturbation of transcription initiation was used to determine Pol II turnover rate in both species. Integration of these data into the model shows that infrequent Pol II occupancy in mouse is explained by the combination of high Pol II turnover and low transcription initiation rates.

Thursday, January 15th - Disease Models

Xiao, G., Li, Y., Hu, Y., Tan, K., Wang, M., Zhu, K., San, M., Cheng, Q., Tayier, D., Hu, T., Dang, P., Li, J., Cheng, C., Perrimon, N., Yang, Z., Song, W. (2025). Intratumor HIF-1alpha modulates production of a cachectic ligand to cause host wasting. Cell Insight, 4(3):100247 PubMed ID: 40336592
Summary:
Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. This study used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, this study found that hypoxia-inducible factor HIF-1&alpah;/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1&alpha/Sima activity in adult yki (3SA) gut tumors or larval scrib¹ Ras^V12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. This study further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, this study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia.

Villalobos-Cantor, S., Arreola-Bustos, A., Martin, I. (2025). Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila. Genetics, 230(3) PubMed ID: 40343931
Summary:
Parkinson's disease (PD) is thought to develop through a complex interplay of genetic and environmental factors. Epidemiological studies have linked exposure to certain pesticides such as paraquat with elevated PD risk, although how a person's genetic makeup influences disease risk upon exposure remains unknown. Here, we used a genome-wide approach to uncover genes that play a role in resistance to paraquat-induced dopaminergic (DA) neurodegeneration in Drosophila. This study developed a paraquat exposure model displaying delayed-onset DA neurodegeneration to recapitulate this aspect of human disease. Genetic background proves to be a strong determinant of paraquat-induced DA neurodegeneration susceptibility across a series of nearly 200 fly strains called the Drosophila Genetic Reference Panel. Through unbiased genome-wide analysis and follow-up validation, two candidate paraquat resistance genes, luna and CG32264. In gene-level studies, decreased expression of luna or CG32264 is associated with paraquat-induced DA neuron loss while overexpression of either gene prevents neurodegeneration in vivo. The mammalian ortholog of CG32264 is Phactr2, which has previously been linked to idiopathic PD risk in several populations. Hence, these results reveal genes regulating paraquat-induced DA neuron loss that intersect with human PD risk variants, supporting the potential relevance of our findings to PD and underscoring a role for gene-environment interactions in pesticide-related DA neurodegeneration.

Adebambo, T. H., Medina-Flores, F., Zhang, S., Lerit, D. A. (2025). Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model. G3 (Bethesda), 15(5) PubMed ID: 40192438
Summary:
Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. This study examined the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, significant developmental delays and heightened mortality were identified in response to arsenic. Within the developing larval brain, a dose-dependent increase in brain volume was identified. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Bhatnagar, A., Thomas, C. M., Nge, G. G., Zaya, A., Dasari, R., Chongtham, N., Manandhar, B., Kortagere, S., Elefant, F. (2025). Tip60 HAT activators as therapeutic modulators for Alzheimer's disease. Nat Commun, 16(1):3347 PubMed ID: 40199891
Summary:
Reduced histone acetylation in the brain causes transcriptional dysregulation and cognitive impairment that are key initial steps in Alzheimer's disease (AD) etiology. Unfortunately, current treatment strategies primarily focus on histone deacetylase inhibition (HDACi) that causes detrimental side effects due to non-specific acetylation. This study testd Tip60 histone acetyltransferase (HAT) activation as a therapeutic strategy for selectively restoring cognition-associated histone acetylation depleted in AD by developing compounds that enhance Tip60's neuroprotective HAT function. Several compounds show high Tip60-binding affinity predictions in silico, enhanced Tip60 HAT action in vitro, and restore Tip60 knockdown mediated functional deficits in Drosophila in vivo. Furthermore, compounds prevent neuronal deficits and lethality in an AD-associated amyloid precursor protein neurodegenerative Drosophila model and remarkably, restore expression of repressed neuroplasticity genes in the AD brain, underscoring compound specificity and therapeutic effectiveness. These results highlight Tip60 HAT activators as a promising therapeutic neuroepigenetic modulator strategy for AD treatment.

Toure, H., Durand, N., Orgeur, M., Galindo, L. A., Girard-Misguich, F., GuEnal, I., Herrmann, J. L., Szuplewski, S. (2025). ENaC is a host susceptibility factor to bacterial infections in cystic fibrosis context. Commun Biol, 8(1):653 PubMed ID: 40269088
Summary:
Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, advantage was taken of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+). ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, these results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens.

Yan, J., Feng, C., Zhang, H., Luo, T., Chen, H., Chen, H. (2025). Dapagliflozin ameliorates intestinal stem cell aging by regulating the MAPK signaling pathway in Drosophila. Front Cell Dev Biol, 13:1576258 PubMed ID: 40337552
Summary:
Intestinal stem cells (ISCs) possess the ability to self-renew and differentiate, which is essential for maintaining intestinal tissue homeostasis. However, their functionality significantly declines with age, leading to diminished tissue regeneration and an increased risk of age-associated diseases. This study investigates the effects of Dapagliflozin (DAPA), a novel insulin sensitizer and SGLT2 inhibitor, on aging ISCs using the Drosophila melanogaster model. The findings demonstrate that Dapagliflozin (Farxiga) DAPA can inhibit the MAPK signaling pathway, as confirmed by network pharmacology analysis and molecular docking experiments. DAPA ameliorates ISC aging, improves intestinal function (including enhanced fecal excretion, restored intestinal barrier integrity and acid-base balance), and enhances healthspan. These results highlight the potential of DAPA as an anti-aging therapeutic agent. This study provides new evidence for the application of DAPA as an anti-aging treatment.

Wednesday, January 14th - Behavior

Brudner, S., Zhou, B., Jayaram, V., Santana, G. M., Clark, D. A., Emonet, T. (2025). Fly navigational responses to odor motion and gradient cues are tuned to plume statistics. bioRxiv, PubMed ID: 40235995
Summary:
Odor cues guide animals to food and mates. Different environmental conditions can create differently patterned odor plumes, making navigation more challenging. Prior work has shown that animals turn upwind when they detect odor and cast crosswind when they lose it. Animals with bilateral olfactory sensors can also detect directional odor cues, such as odor gradient and odor motion. It remains unknown how animals use these two directional odor cues to guide crosswind navigation in odor plumes with distinct statistics. This problem was investigated theoretically and experimentally. These directional odor cues provide complementary information for navigation in different plume environments. We numerically analyzed real plumes to show that odor gradient cues are more informative about crosswind directions in relatively smooth odor plumes, while odor motion cues are more informative in turbulent or complex plumes. Neural networks trained to optimize crosswind turning converge to distinctive network structures that are tuned to odor gradient cues in smooth plumes and to odor motion cues in complex plumes. These trained networks improve the performance of artificial agents navigating plume environments that match the training environment. By recording Drosophila as they navigated different odor plume environments, this study verified that flies show the same correspondence between informative cues and plume types. Fly turning in the crosswind direction is correlated with odor gradients in smooth plumes and with odor motion in complex plumes. Overall, these results demonstrate that these directional odor cues are complementary across environments, and that animals exploit this relationship.

Philyaw, T. J., Titos, I., Cummins-Beebee, P. N., Rodan, A. R., Rothenfluh, A. (2025). Bitter Sensing Protects Drosophila from Developing Experience-Dependent Cocaine Consumption Preference. J Neurosci, 45(27) PubMed ID: 40456609
Summary:
Cocaine is an addictive psychostimulant, and the risk of developing cocaine use disorder (CUD) is highly heritable. Little is known about the specific genes and mechanisms that lead to the development of CUD, and there are currently no FDA-approved pharmacotherapies that can treat it. Drosophila has proven an effective model organism to identify genes and mechanisms underlying addiction, especially alcohol use disorder. While flies exposed to cocaine display features of acute intoxication like those observed in mammals, including hyperactivity and reduced sleep, to date, there is no model of preferential cocaine self-administration in flies. This study assayed cocaine consumption in Drosophila males, as well as preference in a two-choice paradigm. Mechanisms were investigated involved in cocaine taste sensing using genetic and imaging tools. Cocaine is shown to be innately aversive to flies and that this avoidance depends on bitter sensing. Gustatory sensory neurons expressing the Gr66a bitter receptor are activated upon exposure to cocaine. Silencing of these bitter-sensing neurons or mutation of Gr66a reduces cocaine avoidance. In a longitudinal choice assay, these flies develop preference for cocaine-containing solutions within 12-18 h, whereas control flies do not. These findings show that bitter sensation protects flies from developing cocaine self-administration preference. Conversely, silencing bitter perception enables use of Drosophila as a model for experience-dependent cocaine self-administration preference. This opens the door to testing human variants associated with CUD for their causative role in cocaine self-administration in this highly tractable model organism.

Macartney, E. L., Burke, S., Pottier, P., Hamoudi, Z., Hart, C., Ahmed, R., Lin, Y. Q., Neely, G. G., Drobniak, S. M., Nakagawa, S. (2025). Sex-Specific Effects of Social Environment on Behaviour and Their Correlations in Drosophila melanogaster. Ecol Evol, 15(4):e71261 PubMed ID: 40290389
Summary:
Environmental and individual experiences can result in immediate and persistent changes in behaviour. Often, such effects are also sex-dependent. Intraspecific interactions can be one of the most important environments an individual faces. Such social interactions are expected to affect a suite of behavioural traits and their correlations. This study used Drosophila melanogaster and high-throughput automated behavioural phenotyping to determine how social environment (group mixed sex, group single sex, and social isolation) and sex interact to affect basic behaviours (exploration, movement within a y-maze, and habituation to a startle) that likely underlie more complex behaviours such as mate searching and foraging. Such behaviours and some behavioural correlations were shown to be context- and sex-dependent. Males tended to show greater exploration, while females were more likely to show a habituation response to startle. Males and females from the mixed sex and isolated treatments showed opposite exploratory behaviour in the Y-maze, and social treatment interacted with sex to affect the rate of habituation to a startle. Females also tended to have slightly stronger trait correlations compared to males. These results show that social environment and sex can play a significant role in shaping behaviour in Drosophila melanogaster. This study provides insights into how the type of social stimulation and sex can interact to affect behaviours that are important in forming critical behaviours related to foraging and mate searching.

Wu, Z., Wu, X., Wang, Z., Ye, X., Pang, L., Wang, Y., Zhou, Y., Chen, T., Zhou, S., Wang, Z., Sheng, Y., Zhang, Q., Chen, J., Tang, P., Shen, X., Huang, J., Drezen, J. M., Strand, M. R., Chen, X. (2025). A symbiotic gene stimulates aggressive behavior favoring the survival of parasitized caterpillars. Proc Natl Acad Sci U S A, 122(18):e2422935122 PubMed ID: 40294273
Summary:
Animals often exhibit increased aggression in response to starvation, while parasites often manipulate host behavior. In contrast, underlying molecular mechanisms for these behavioral changes are mostly unknown. The diamondback moth, Plutella xylostella, is an agricultural pest that feeds on cruciferous plants as larvae, while Cotesia vestalis is a parasitoid wasp that parasitizes diamondback moth larvae. In this study, we determined that unparasitized diamondback moth larvae exhibit increased aggression and cannibalism when starved, while starved larvae parasitized by C. vestalis were more aggressive than unparasitized larvae. C. vestalis harbors a domesticated endogenized virus named Cotesia vestalis bracovirus (CvBV) that wasps inject into parasitized hosts. Starvation increased octopamine (OA) levels in the central nervous system (CNS) of diamondback moth larvae while a series of experiments identified a CvBV-encoded gene product named Assailant that further increased aggression in starved diamondback moth larvae. We determined that Assailant increases OA levels by activating tyramine beta-hydroxylase (PxTβh), which is a key enzyme in the OA biosynthesis pathway. Ectopic expression of assailant in Drosophila melanogaster likewise upregulated expression of DmTβh and OA, which increased aggressive behavior in male flies as measured by a well-established assay. While parasitized hosts are often thought to be at a competitive disadvantage to nonparasitized individuals, these results uncover how a parasitoid uses an endogenized virus to increase host aggression and enhance survival of offspring when competing against unparasitized hosts.

Vaxenburg, R., Siwanowicz, I., Merel, J., Robie, A. A., Morrow, C., Novati, G., Stefanidi, Z., Both, G. J., Card, G. M., Reiser, M. B., Botvinick, M. M., Branson, K. M., Tassa, Y., Turaga, S. C. (2025). Whole-body physics simulation of fruit fly locomotion. Nature, PubMed ID: 40267984
Summary:
The body of an animal influences how its nervous system generates behaviour. Accurately modelling the neural control of sensorimotor behaviour requires an anatomically detailed biomechanical representation of the body. This study introduces a whole-body model of the fruit fly Drosophila melanogaster in a physics simulator. Designed as a general-purpose framework, this model enables the simulation of diverse fly behaviours, including both terrestrial and aerial locomotion. Its versatility was validated by replicating realistic walking and flight behaviours. To support these behaviours, phenomenological models were developfor fluid and adhesion forces. Using data-driven, end-to-end reinforcement learning, neural network controllers capable of generating naturalistic locomotion were train along complex trajectories in response to high-level steering commands. Furthermore, this study showed the use of visual sensors and hierarchical motor control, training a high-level controller to reuse a pretrained low-level flight controller to perform visually guided flight tasks. This model serves as an open-source platform for studying the neural control of sensorimotor behaviour in an embodied context.

Yoshino, J., Mali, S. S., Williams, C. R., Morita, T., Emerson, C. E., Arp, C. J., Miller, S. E., Yin, C., The, L., Hemmi, C., Motoyoshi, M., Ishii, K., Emoto, K., Bautista, D. M., Parrish, J. Z. (2025). Drosophila epidermal cells are intrinsically mechanosensitive and modulate nociceptive behavioral outputs. Elife, 13 PubMed ID: 40353351
Summary:
Somatosensory neurons (SSNs) that detect and transduce mechanical, thermal, and chemical stimuli densely innervate an animal's skin. However, although epidermal cells provide the first point of contact for sensory stimuli, understanding of roles that epidermal cells play in SSN function, particularly nociception, remains limited. This study show that stimulating Drosophila epidermal cells elicits activation of SSNs including nociceptors and triggers a variety of behavior outputs, including avoidance and escape. Further, this study found that epidermal cells are intrinsically mechanosensitive and that epidermal mechanically evoked calcium responses require the store-operated calcium channel Orai. Epidermal cell stimulation augments larval responses to acute nociceptive stimuli and promotes prolonged hypersensitivity to subsequent mechanical stimuli. Hence, epidermal cells are key determinants of nociceptive sensitivity and sensitization, acting as primary sensors of noxious stimuli that tune nociceptor output and drive protective behaviors.

Monday, January 12th - Adult Physiology and Meteabolism

Wang, C., Shen, J. (2025). From metabolism to lifespan trade-offs: polyethylene microplastics induce circadian disruption and sex-specific aging in Drosophila melanogaster. Comp Biochem Physiol C Toxicol Pharmacol, 295:110214 PubMed ID: 40300706
Summary:
Microplastics (MPs), particularly polyethylene microplastics (PE-MPs), are increasingly recognized as contaminants in both aquatic and terrestrial environments. However, the ecological impacts of PE-MPs on terrestrial organisms remain underexplored. This study investigates the physiological and behavioral effects of PE-MPs exposure in Drosophila melanogaster, shedding light on the potential risks posed by PE-MPs in land-based ecosystems. After exposing the fruit flies to different concentrations of PE-MPs for 20 days, several physiological biomarkers were assessed, including spontaneous behavioral activity, starvation resistance, metabolic biomarkers, and lifespan. The findings indicate that PE-MPs exposure significantly affects fruit fly physiology, with increased spontaneous activity, decreased starvation resistance, and reduced triglyceride (TG) and protein levels (in males), reflecting disruption of metabolic processes. While PE-MPs did not affect female reproductive capacity, they did result in sex-specific impacts on lifespan, with male fruit flies showing a significant reduction in both mean and median lifespan at higher PE-MPs concentrations. These results highlight the need to consider the sex-dependent nature of PE-MPs toxicity when assessing their ecological risks. This study contributes new insights into the potential for PE-MPs to disrupt terrestrial ecosystems and underscores the importance of investigating the effects of microplastics on terrestrial invertebrates, providing a foundation for future ecotoxicological research.

Rossano, A. J., Zhang, L., Anderson, J. B., Holmes, H. L., Mandal, A. K., Decker, J. W., Mount, D. B., Romero, M. F. (2025). Ex vivo quantification of intracellular pH in Drosophila Malpighian tubule reveals basolateral HCO(3) (-)/oxalate exchange through a novel oxalate transporter "Neat". Front Physiol, 16:1468451 PubMed ID: 40356774
Summary:
Nephrolithiasis is a painful and costly healthcare complication. The most common kidney stones are composed of calcium oxalate and thus renal handling of oxalate is an important facet of understanding the pathogenesis of nephrolithiasis. Recently, the Drosophila melanogaster Malpighian tubule (MT) has emerged as a robust model of trans-epithelial ion transport and nephrolithiasis as MTs readily form luminal calcium-oxalate crystals in the presence of oxalate. Drosophila Prestin (dPrestin, Slc26a6) transports oxalate across the apical surface of the MT into the lumen. The objective of this work was to identify and characterize the Drosophila basolateral Ox(2-) transporter through ex vivo real-time quantification of intracellular pH (pH(i)). A putative basolateral oxalate transporter "CG5002 ("Neat") was identified through sequence homology and displayed robust Cl(-)-independent Ox(2-) transport and electroneutral Ox(2-) transport in Xenopus oocytes. pH(i) in extracted fly MTs was monitored. Basolateral perfusion of MTs in CO(2)/HCO(3) (-)-buffered solution produced a large acidification followed by rapid recovery in the transitional segment of the anterior MT. Recovery was interrupted by basolateral application of 1 mM Ox(2-) or 1 mM SO(4). Tissue specific knock-down of Neat with interference RNA (RNAi) reduced the rate of acid-loading in the transitional segment of the MT with regard to Ox(2-) and SO(4). Knockdown of Neat in the MT also significantly reduced luminal calcium oxalate crystal formation in a fly ex vivo model of calcium oxalate nephrolithiasis. These data indicate Neat is a significant Drosophila basolateral MT oxalate transporter and the basolateral movement of oxalate is functionally coupled to movement of acid equivalents, potentially as Ox(2-)/HCO(3) (-) exchange, Ox(2-)/OH(-) exchange, or Ox(2-):H(+) co-transport.

Rai, M., Li, H., Policastro, R. A., Pepin, R., Zentner, G. E., Nemkov, T., D'Alessandro, A., Tennessen, J. M. (2025). Glycolytic disruption restricts Drosophila melanogaster larval growth via the cytokine Upd3. PLoS Genet, 21(5):e1011690 PubMed ID: 40315265
Summary:
Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate dehydrogenase (Ldh) and glycerol-3-phosphate dehydrogenase (Gpdh1) support this larval metabolic program by cooperatively promoting glycolytic flux. Consistent with their cooperative functions, the loss of both enzymes, but not either single enzyme alone, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the lethal phenotypes exhibited by Gpdh1; Ldh double mutants could be mediated non-autonomously. Supporting this possibility, the developmental arrest displayed by double mutants was found to extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, it was demonstrated that the simultaneous loss of Gpdh1 and Ldh results in elevated expression of Upd3, a cytokine involved in Jak/Stat signaling. Furthermore, upd3 loss-of-function mutations was shown to suppress the Gpdh1; Ldh larval arrest phenotype, indicating that Upd3 signaling restricts larval development in response to decreased glycolytic flux. Together, these findings reveal a mechanism by which metabolic disruptions can modulate systemic growth factor signaling.

Van De Poll, M. N., van Swinderen, B. (2025). Long-term multichannel recordings in Drosophila flies reveal altered predictive processing during sleep compared with wake. J Exp Biol, 228(11) PubMed ID: 40296777
Summary:
During sleep, behavioral responsiveness to external stimuli is decreased. This classical definition of sleep has been applied effectively across the animal kingdom to identify this common behavioral state in a growing list of creatures, from mammals to invertebrates. Yet, it remains unclear whether decreased behavioral responsiveness during sleep is necessarily associated with decreased responsiveness in brain activity, especially in insects. Long-term multichannel electrophysiology was performed in tethered Drosophila melanogaster flies exposed continuously to repetitive visual stimuli. Flies were still able to sleep under these visual stimulation conditions, as determined by traditional immobility duration criteria for the field. Interestingly, this study did not find any difference between responses to repetitive visual stimuli during sleep compared with wake when we recorded local field potentials (LFPs) across a transect of the fly brain from optic lobes to the central brain. However, LFP responses were found to be altered when visual stimuli were variable and of lower probability, especially in the central brain. Central brain responses to less predictable or 'deviant' stimuli were lower during the deepest stage of sleep, a time of quiescence characterized by more regular proboscis extensions. This shows that the sleeping fly brain processes low-probability visual stimuli in a different way from more repeated stimuli, and presents Drosophila as a promising model for studying the potential role of sleep in regulating predictive processing.

Yu, G., Yang, Q., Wu, Q. (2025). Rapamycin Alters the Feeding Preference for Amino Acids and Sugar in Female Drosophila. J Gerontol A Biol Sci Med Sci, 80(7) PubMed ID: 40296844
Summary:
Rapamycin has demonstrated significant lifespan-extending effects across a variety of model organisms, positioning it as one of the most promising antiaging agents currently under investigation. Nonetheless, chronic administration of rapamycin may induce diverse adverse reactions, primarily due to its influence on energy metabolism. Using Drosophila melanogaster as a model, this study showed that rapamycin significantly alters feeding behaviors in a dose-dependent manner. Specifically, both long-term and short-term administration of the optimal life-extending dose of rapamycin decreases the protein preference while increasing sugar intake in female flies. Utilizing a chemically defined diet, these alterations in amino acid and sugar feeding preferences were shown to occur as early as the second day of rapamycin exposure, preceding any detectable decline in fecundity. Furthermore, rapamycin also modifies amino acid preference even in taste-blind females, indicating that postingestive nutritional learning mechanisms, independent of food taste value, are sufficient to mediate the effects of rapamycin on feeding behavior. However, such changes in macronutrient preferences were absent in males and sterile mutant females. Collectively, this study suggests that the modification of feeding behavior could be a non-negligible side effect of rapamycin treatment, and this effect is influenced by both sex and reproductive status.

Subaric, D., Rastija, V., Karnas Babi , M., Agic, D., Majic, I. (2025). Structural Features of Coumarin-1,2,4-Triazole Hybrids Important for Insecticidal Effects Against Drosophila melanogaster and Orius laevigatus (Fieber). Molecules, 30(8) PubMed ID: 40333563
Summary:
Although the present use of pesticides in plant protection has limited the occurrence and development of plant diseases and pests, resistance to pesticides and their environmental and health hazards indicates an urgent need for new active ingredients in plant protection products. Recently synthesized coumarin-1,2,4-triazole hybrid compounds have been proven effective against plant pathogenic fungi and safe for soil-beneficial bacteria. Drosophila melanogaster, the common fruit fly, has been used as a model organism for scientific research. Additionally, it is considered a pest since it damages fruits and serves as a carrier for various plant diseases. On the contrary, Orius laevigatus is a beneficial true bug that biologically controls harmful arthropods in agricultural production. In the present study, an adulticidal bioassay was performed against D. melanogaster and O. laevigatus using coumarin-1,2,4-triazole hybrids. Quantitative structure-activity relationship studies (QSARs) and in silico ecotoxicity evaluation elucidated the structural features underlying the compounds' insecticidal activity. The derivative of 4-methylcoumarin-1,2,4-triazole with a 3-bromophenyl group showed great insecticidal potential. A molecular docking study indicated that the most active compound probably binds to glutamate-gated chloride channels.

Thursday, January 8th - Disease models

Ti, X., Zuo, H., Zhao, G., Li, Y., Du, M., Xu, L., Li, S., Shan, Z., Gao, Y., Gan, G., Wang, Y., Zhang, Q. (2025). Parkin mediates the mitochondrial dysfunction through mRpL18. J Biol Chem, 301(6):110208 PubMed ID: 40345588
Summary:
Loss of function of parkin leads to mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One dogma is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, the first dogma is not applicable; for the second dogma, this study suggests that Parkin mediates mitochondrial dysfunction through the synergy of both Marf and mitochondrial protein mRpL18 got from a genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, this study found that impaired Parkin upregulated both transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing mRpL18 accumulation outside mitochondria. Consequently, cytosolic-accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways together drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, this study unveils a new facet of how Parkin regulates mitochondrial morphology, which provides new insights for the understanding and treatment of Parkinson's disease.

Scudese, E., Marshall, A. G., Vue, Z., Exil, V., ..., Sharma, V., Mobley, B. C., Katti, P., Hinton, A. (2025). 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes. Aging Cell:e70054 PubMed ID: 40285369
Summary:
Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. This study sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers were correlate between young (under 50 years) and old (over 50 years) individuals. Mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which this study showed is required for the integrity of mitochondrial structure. Furthermore, this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. These results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Tan, S. L., Neumann, D., Trim, P. J., Hewson, L. J., Mustaffar, N. F., He, Q. Q., Wimmer, N., Snel, M. F., Ferro, V., O'Keefe, L. V., Hemsley, K. M., Lau, A. A. (2025). Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome. Mol Genet Metab, 145(2):109112 PubMed ID: 40288156
Summary:
Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). This study tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC Drosophila fed 4-deoxy-N-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders.

Singh, K., Gupta, K., Shukla, S., Kumari, A. P., Kumar, A. (2025). Repurposing Oseltamivir Against CAG Repeat Mediated Toxicity in Huntington's Disease and Spinocerebellar Ataxia Using Cellular and Drosophila Model. ACS Omega, 10(15):14980-14993 PubMed ID: 40290909
Summary:
Huntington's disease (HD) and Spinocerebellar Ataxia (SCA) are debilitating neurological disorders triggered by the expansion of CAG sequences within the specific genes (HTT and ATXN, respectively). These are characterized as poly glutamine (polyQ) disorders, which are marked by widespread neurodegeneration and metabolic irregularities across systemic, cellular, and intracellular levels. This study aimed to identify small molecules that specifically interact with and target the toxic CAG repeat RNA. This study investigated the neuroprotective effects of Oseltamivir, an antiviral drug, against the HD and SCA-causing CAG repeats, through biophysical, cellular, and Drosophila model-based studies. Using a multidimensional approach encompassing biophysical techniques, cellular assays, and a Drosophila model, Oseltamivir's interaction with toxic CAG repeat RNA was explored. These comprehensive analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), and nuclear magnetic resonance (NMR) spectroscopy, demonstrated Oseltamivir's specific binding affinity for AA mismatches and its potential to mitigate the toxicity associated with polyQ aggregation. Moreover, the identified U.S. FDA-approved drug effectively mitigated polyQ-induced toxicity in both HD cells and the Drosophila model of the disease. The results obtained from this drug repurposing approach are indicative of the neuro-shielding role of Oseltamivir in HD and several SCAs, paving the way for its translation into clinical practice to benefit patients afflicted with these devastating diseases.

Song, H., Kim, S., Han, J. E., Kang, K. H., Koh, H. (2025). PDH Inhibition in Drosophila Ameliorates Sensory Dysfunction Induced by Vincristine Treatment in the Chemotherapy-Induced Peripheral Neuropathy Models. Biomedicines, 13(4) PubMed ID: 40299339
Summary:
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting side effect of many effective anticancer agents, including vincristine. While CIPN adversely affects both oncological outcomes and the quality of life for cancer patients, the in vivo mechanisms behind CIPN pathology remain largely unknown, and effective treatments have yet to be developed. This study established a novel Drosophila model of CIPN using vincristine to explore the molecular mechanisms underlying this condition. The impact of vincristine exposure on thermal nociception in Drosophila larvae was assessed using a programmable heat probe. Additionally, vincristine-induced mitochondrial dysfunction and dendritic abnormalities in class IV dendritic arborization (C4da) neurons was investigated with various fluorescent protein markers. A dose-dependent increase in thermal hypersensitivity was found, accompanied by changes in the sensory dendrites of C4da neurons in vincristine-treated fly larvae. Moreover, vincristine significantly enhanced mitochondrial ROS production and mitophagy-a selective autophagy that targets dysfunctional mitochondria-indicating vincristine-induced mitochondrial dysfunction within C4da neurons. Surprisingly, inhibiting the pyruvate dehydrogenase complex (PDH), a key mitochondrial metabolic enzyme complex, effectively rescued the mitochondrial and sensory abnormalities caused by vincristine.Findings from this first Drosophila model of vincristine-induced peripheral neuropathy (VIPN) suggest that mitochondrial dysfunction plays a critical role in VIPN pathology, representing PDH as a potential target for the treatment of VIPN.

Serebryany-Piavsky, V., Egulsky, L., Manoim-Wolkovitz, J. E., Anis, S., Hassin-Baer, S., Parnas, M., Horowitz, M. (2025). The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease. Hum Mol Genet, 34(14):1184-1203 PubMed ID: 40315377
Summary:
Parkinson disease (PD) is the second most common neurodegenerative disease. While most cases are sporadic, in ~5%-10% of PD patients the disease is caused by mutations in several genes, among them GBA1 (glucocerebrosidase beta 1) and LRRK2 (leucine-rich repeat kinase 2), both prevalent among the Ashkenazi Jewish population. LRRK2-associated PD tends to be milder than GBA1-associated PD. Several recent clinical studies have suggested that carriers of both GBA1 and LRRK2 mutations develop milder PD compared to that observed among GBA1 carriers. These findings strongly suggested an interplay between the two genes in the development and progression of PD. In the present study Drosophila was employed as a model to investigate the impact of mutations in the LRRK2 gene on mutant GBA1-associated PD. The results strongly indicated that flies expressing both mutant genes exhibited milder parkinsonian signs compared to the disease developed in flies expressing only a GBA1 mutation. This was corroborated by a decrease in the ER stress response, increase in the number of dopaminergic cells, elevated levels of tyrosine hydroxylase, reduced neuroinflammation, improved locomotion and extended survival. Furthermore, a significant decrease in the steady-state levels of mutant GBA1-encoded GCase was observed in the presence of mutant LRRK2, strongly implying a role for mutant LRRK2 in degradation of mutant GCase.

Monday, January 5th - Larval and Adult Development

Lee, U., Li, C., Langer, C. B., Svetec, N., Zhao, L. (2025). Comparative single-cell analysis of transcriptional bursting reveals the role of genome organization in de novo transcript origination. Proc Natl Acad Sci U S A, 122(18):e2425618122 PubMed ID: 40305051
Summary:
Spermatogenesis is a key developmental process underlying the origination of newly evolved genes. However, rapid cell type-specific transcriptomic divergence of the Drosophila germline has posed a significant technical barrier for comparative single-cell RNA-sequencing studies. By quantifying a surprisingly strong correlation between species- and cell type-specific divergence in three closely related Drosophila species, a statistical procedure was applied to identify a core set of 198 genes that are highly predictive of cell type identity while remaining robust to species-specific differences that span over 25 to 30 My of evolution. Then cell type classifications based on the 198-gene set were used to show how transcriptional. divergence in cell type increases throughout spermatogenic developmental time. After validating these cross-species cell type classifications using RNA fluorescence in situ hybridization and imaging, this study then investigated the influence of genome organization on the molecular evolution of spermatogenesis vis-a-vis transcriptional bursting. Altering transcriptional burst size was shown to contribute to premeiotic transcription and altering bursting frequency contributes to postmeiotic expression. Global differences in autosomal vs. X chromosomal transcription may arise in a developmental stage preceding full testis organogenesis were illustrated by showing evolutionarily conserved decreases in X-linked transcription bursting kinetics in all examined somatic and germline cell types. Finally, evidence is provided supporting the cultivator model of de novo gene origination by demonstrating how the appearance of newly evolved testis-specific transcripts potentially provides short-range regulation of neighboring genes' transcriptional bursting properties during key stages of spermatogenesis.

Wang, L., Bu, T., Gao, S., Yun, D., Chen, H., Cheng, C. Y., Sun, F. (2025). PCP protein Prickle 1 regulates Sertoli cell and testis function via cytoskeletal organization through the recruitment of multiple regulatory proteins. Am J Physiol Cell Physiol, 328(6):C2032-c2056 PubMed ID: 40327382
Summary:
Prickle 1, an ortholog found in Drosophila, was localized at the Sertoli cell-spermatid interface consistent with its role of supporting the Vangl2 planar cell polarity (PCP), which is an integral membrane protein that creates the PCP protein complex of Vangl2 (Van Gogh-like 2)/Prickle1. Together with the asymmetrically localized transmembrane protein Frizzled (Fzd) and its unique adaptor proteins Disheveled (Dvl) and Inversin (Inv), Vangl2/Prickle1 and Fzd/Dvl/Inv are the two heterodimeric interacting PCP proteins between Sertoli cells and condensed spermatids to confer spermatid PCP across the plane of the seminiferous epithelium. The initial intention of this work was to examine if the distribution and expression of Prickle1 using a primary Sertoli cell in vitro model and Sprague-Dawley rats in vivo would mimic much of the earlier reported findings of Vangl2. Unexpectedly, these findings indicated that Prickle1 supported the PCP protein Vangl2; however, Prickle1 is also a multifunctional protein. First, Prickle1 knockdown (KD) by RNAi impeded Sertoli cell TJ function by perturbing the distribution of the BTB-associated proteins at the cell-cell interface, through disruption of the microtubule (MT) and actin cytoskeletal organization including their respective polymerization (and/or bundling) capability. Second, these findings were reproduced using an in vivo model of RNAi by KD of Prickle 1 in the testis. Third, using coimmunoprecipitation (Co-IP), Prickle 1 was found to interact with a host of adaptor proteins crucial to support not only PCP, such as Dvl, but also regulatory cytoskeletal proteins of MT and actin networks, including RhoA, Arp3, Cdc42, ZO-1, and β-catenin by immunoprecipitation-mass spectrometry (IP-MS) using the String Protein Interaction Tool.

Ku, H. Y., Bilder, D. (2025). Basement membrane patterning by spatial deployment of a secretion-regulating protease. Proc Natl Acad Sci U S A, 122(20):e2412161122 PubMed ID: 40359035
Summary:
While paradigms for patterning of cell fates in development are well established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are not. Morphogenesis of the Drosophila egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose gradient creates tissue mechanical properties that specify the degree of elongation. This study shows that the gradient is not regulated by Col4 transcription but instead relies on posttranscriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypoelongation. Evidence is presented that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Meanwhile, the terminally expressed metalloprotease Stall increases Col4 turnover in the posterior. These data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape.

Simmons, C., Williams, I. H., Bradshaw, T. W., Armstrong, A. R. (2025). Adipocyte-Derived CCHamide-1, Eiger, Growth-Blocking Peptide 3, and Unpaired 2 Regulate Drosophila melanogaster Oogenesis. Biomolecules, 15(4) PubMed ID: 40305230
Summary:
In addition to energy storage, adipose tissue communication to other organs plays a key role in regulating organismal physiology. While the link between adipose tissue dysfunction and pathophysiology, including diabetes, chronic inflammation, and infertility, is clear, the molecular mechanisms that underlie these associations have not been fully described. This study used Drosophila melanogaster as a model to better understand how adipose tissue communicates to the ovary. This study utilized D. melanogaster's robust genetic toolkit to examine the role of five adipokines known to control larval growth during development, CCHamide-1, CCHamide-2, eiger, Growth-blocking peptide 3, and unpaired 2 in regulating oogenesis. The adult fat body expresses these "larval" adipokines. The data indicate that ovarian germline stem cell maintenance does not require these adipokines. However, adipocyte-derived CCHamide-1, eiger, Growth-blocking peptide 3, and unpaired 2 influence early and late germline survival as well as ovulation. Thus, this work uncovers several adipokines that mediate fat-to-ovary communication.

Peng, J., Sun, A., Zheng, J., Zhang, N., Zhang, X., Gao, G. (2025). Testis-specific serine/threonine kinase dTSSK2 regulates sperm motility and male fertility in Drosophila. Commun Biol, 8(1):710 PubMed ID: 40335644
Summary:
Serine/threonine kinases of the TSSK (Testis-Specific Serine/Threonine Kinase) family play crucial roles in spermatogenesis and male fertility across species, but the underlying regulatory mechanism remains incompletely understood. In this study, we identified and characterized a novel TSSK homolog in Drosophila, named dTSSK2 (CG9222), which functions as the ortholog of human TSSK4. dTSSK2 is specifically expressed in the testis and localizes to individualization complexes during spermiogenesis. Disruption of dTSSK2 severely compromises sperm motility, leading to failed sperm transit into the seminal vesicle and male infertility. Phosphoproteomic analyses reveal that dTSSK2 coordinates sperm flagella assembly and motility by phosphorylating proteins involved in microtubule organization, organelle assembly, and flagella structure. Notably, dTSSK2 phosphorylates the substrate Gudu at Ser9, which partially contributes to individualization complex integrity and sperm motility. These findings elucidate the critical role of dTSSK2-mediated phosphorylation in regulating Drosophila male fertility.

Otsune, S., Matsuka, M., Shirakashi, C., Zhang, X., Nakagoshi, H. (2025). Polished Rice Regulates Maturation but Not Survival of Secondary Cells in Drosophila Male Accessory Gland. Genes Cells, 30(3):e70025 PubMed ID: 40346918
Summary:
In Drosophila males, the accessory gland is responsive to nutrient signal-dependent regulation of fertility/fecundity. The accessory gland is composed of two types of binucleated epithelial cells, about 1000 main cells and 60 secondary cells (SCs). The transcription factors Defective proventriculus (Dve), XF../segment/abdomlb1.htm">Abdominal-B, and Ecdysone receptors (EcRs) are strongly expressed in adult SCs. In response to nutrient conditions during development, coordinated action between Dve and ecdysone signaling determines the optimal number of SCs and regulates their maturation. A downstream effector of ecdysone signaling, Ftz-F1, is crucial in this process. Another downstream effector, Polished rice (Pri), is small peptides of 11 or 32 amino acids. This study shows that pri is required for maturation of SCs and for male fecundity, whereas it is not involved in determination of the number of SCs. Evidence is provided that Pri acts downstream of Ftz-F1 to regulate maturation but not survival of SCs.

Monday,January 5th - Larval and Adult Development

Harsh, S., Liu, H. Y., Bhaskar, P. K., Rushlow, C., Bach, E. A. (2025). Post-transcriptional suppression of the pioneer factor Zelda protects the adult Drosophila testis from activation of the ovary program. PLoS Biol, 23(12):e3003535 PubMed ID: 41411219
Summary:
Maintenance of somatic sex identity is essential for adult tissue function. In the Drosophila testis, adult somatic stem cells known as cyst stem cells (CySCs) require the transcription factor Chinmo to preserve male identity. Loss of Chinmo leads to reprogramming of CySCs into their ovarian counterparts through induction of the female-specific RNA-binding protein TransformerF (TraF), though the underlying mechanism has remained unclear. This study identified the pioneer transcription factor Zelda (Zld) as a critical mediator of this sex reversal. In wild-type CySCs, zld mRNA is repressed by microRNAs (miRs), but following Chinmo loss, these miRs are downregulated, allowing zld mRNA to be translated. Zld is necessary for feminization of chinmo-mutant CySCs, and ectopic expression of Zld in wild-type CySCs is sufficient to induce TraF and drive female reprogramming. Two Zld target genes, qkr58E-2 and Ecdysone receptor (EcR), are upregulated in chinmo-mutant CySCs and are normally female-biased in adult gonads. Qkr58E-2 facilitates TraF production, while EcR promotes female gene expression programs. Zld overexpression feminizes otherwise wild-type CySCs by upregulating EcR, which in turn downregulates the chinmo gene. Strikingly, overexpression of Zld also feminizes adult male adipose tissue by inducing TraF and downregulating Chinmo, indicating that Zld can override male identity in multiple adult XY tissues. Together, these findings uncover a post-transcriptional mechanism in which miRs-mediated repression of a pioneer factor safeguards male identity and prevents inappropriate activation of the female program in adult somatic cells.

Song, Y., Martin, P., Sun, T., Fernandez-Herrero, J., Sanchez-Herrero, E., Pastor-Pareja, J. C. (2025). Mechanical coupling between dorsal and ventral surfaces shapes the Drosophila haltere. Curr Biol, 35(13):3090-3105.e3095 PubMed ID: 40505664
Summary:
The extracellular matrix is an essential determinant of animal form, enabling organization of cells and tissues into organs with complex shapes. In contrast with the dorso-ventrally flat Drosophila wing, its serial homolog, the haltere, adopts a globular shape thought to arise from a lack of matrix-mediated adhesion between its dorsal and ventral surfaces. Contradicting this model, however, matrix manipulations are known to deform halteres. To understand haltere morphogenesis, this study characterized matrix behavior and monitored metamorphic development of the haltere. Similar to the wing, correct haltere morphogenesis was found to require collagen IV degradation, which is mediated by ecdysone-controlled expression of matrix metalloprotease 2 in both wing and haltere. After collagen IV is degraded, similar again to the wing, dorsal and ventral haltere surfaces establish laminin-mediated contact through long cytoskeletal projections. Furthermore, time-lapse analysis of shape changes in wild-type and mutant halteres indicates that these projections couple the two surfaces through a central tensioner, ensuring load distribution across the whole organ to create a globular shape against tissue-wide deforming forces. These findings reveal an unexpected role for matrix-mediated adhesion in haltere morphogenesis and describe a novel type of matrix-based tensor structure building a 3D shape from 2D epithelia.

Bose, A., Schuster, K., Kodali, C., Sonam, S., Smith-Bolton, R. K. (2025). The pioneer transcription factor Zelda controls the exit from regeneration and restoration of patterning in Drosophila. Sci Adv, 11(23):eads5743 PubMed ID: 40479065
Summary:
Many animals can regenerate tissues after injury. While the initiation of regeneration has been studied extensively, how the damage response ends and normal gene expression returns is unclear. This study found that in Drosophila wing imaginal discs, the pioneer transcription factor Zelda controls the exit from regeneration and return to normal gene expression. Optogenetic inactivation of Zelda during regeneration disrupted patterning, induced cell fate errors, and caused morphological defects yet had no effect on normal wing development. Using Cleavage Under Targets & Release Using Nuclease, targets of Zelda important for the end of regeneration were identified, including genes that control wing margin and vein specification, compartment identity, and cell adhesion. GAGA factor and Fork head similarly coordinate patterning after regeneration and that chromatin regions bound by Zelda increase in accessibility during regeneration. Thus, Zelda orchestrates the transition from regeneration to normal gene expression, highlighting a fundamental difference between developmental and regeneration patterning in the wing disc.

Choi, B. J., Chen, Y. C., Desplan, C. (2025). Retinal Calcium Waves Coordinate Uniform Tissue Patterning of the Drosophila Eye. bioRxiv, PubMed ID: 40501815
Summary:
Optimal neural processing relies on precise tissue patterning across diverse cell types. This study shows that spontaneous calcium waves arise among non-neuronal support cells in the developing Drosophila eye to drive retinal morphogenesis. Waves are initiated by Cad96Ca receptor tyrosine kinase signaling, triggering PLCγ-mediated calcium release from the endoplasmic reticulum. A cell-type-specific 'Innexin-code' coordinates wave propagation through a defined gap junction network among non-neuronal retinal cells, excluding photoreceptors. Wave intensity scales with ommatidial size, triggering stronger Myosin II-driven apical contractions at interommatidial boundaries in larger ommatidia. This size-dependent mechanism compensates for early boundary irregularities, ensuring uniform ommatidial packing critical for precise optical architecture. These findings reveal how synchronized calcium signaling among non-neuronal cells orchestrates tissue patterning in the developing nervous system.

Walker, B. M., Palumbo, R. J., Knutson, B. A. (2025). Tissue-specific requirement of Polr1D in the prothoracic gland for ecdysone-mediated developmental transitions in Drosophila melanogaster. Dev Dyn, PubMed ID: 40317818
Summary:
Polr1D is a shared subunit of RNA Polymerases I and III, which transcribe the rRNA incorporated into ribosomes. Mutations in POLR1D cause Treacher Collins syndrome, a craniofacial disorder that arises from impaired ribosome biogenesis in neural crest cells. Previous work found that RNAi knockdown of Polr1D in several non-neural Drosophila tissues caused developmental defects that phenocopy mutations affecting ecdysone signaling. Ecdysone is a steroid hormone produced in the prothoracic gland (PG) of insects that triggers developmental transitions. This study shows that Polr1D is required for PG development and ecdysone production to facilitate larval developmental transitions. Polr1D RNAi in the PG causes larval developmental arrest due to defective peripheral ecdysone signaling. Polr1D is required for the growth of PG cells and for maintaining nucleolar structure. Polr1D was also shown to be required for the synthesis of mature ribosomes and the production of the Pol III-transcribed 7SK RNA. Furthermore, developmental arrest of Polr1D RNAi larvae and Polr1D mutant (G30R) larvae was partially rescued by treatment with exogenous ecdysone. These results demonstrate a role for Drosophila Polr1D in PG development and suggest that disruptions in human Polr1D might impact additional cell types during development.

Ready, D. F., Chang, H. C. (2025). Drosophila photoreceptor tethering by a laminin-Eys scaffold. iScience, 28(6):112732 PubMed ID: 40520108
Summary:
Visual acuity in Drosophila requires precise photoreceptor alignment along the optical axis, maintained by longitudinal tension between a rigid cornea and a contractile retinal base. This study identified the rhabdomere caps-an extracellular matrix (ECM) structure that links rhabdomere tips to the integrin-decorated basal surfaces of overlying, lens-forming cone cells. Rhabdomere caps form perlecan-filled peaks shaped by a trapezoidal LanB1 (laminin) grid, which mirrors the inter-rhabdomeral space (IRS) contour. This study revealed that Eys (eyes shut), a photoreceptor-secreted proteoglycan essential for IRS formation, guides LanB1 and perlecan deposition by cone cells during pupal development. Disruption of LanB1 results in rhabdomere tip detachment, IRS collapse, and impaired tension transmission. These findings reveal that cone cells and photoreceptors collaboratively sculpt a rigid LanB1 grid that caps and reinforces the distal IRS lumen. This composite ECM structure preserves rhabdomere organization and evenly distributes mechanical forces, ensuring photoreceptor alignment and optical fidelity.

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