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Current papers in developmental biology and gene function
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February 2026 January 2026 December 2025 November 2025 October 2025 September 2025 August2025 July 2025 June2025 June2025 May 2025 April 2025 March 2025 February 2025 January 2025 December 2024 November 2024 October 2024 September 2024 August 2024 July 2024 June 2024 May 2024 April 2024 March 2024 February 2024 January 2024 December 2022 December 2021 December 2020 December 2019 | Jayakrishnan, M., Havlova, M., Veverka, V., Regnard, C., Becker, P. B. (2025). Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers. Nucleic Acids Res, 53(6) PubMed ID: 40164442
Summary: Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard chromatin fiber integrity. In Drosophila, the chromodomain protein MSL3 binds H3K36me3 at X-chromosomal genes to implement dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes. Because depletion of K36me3 had variable, locus-specific effects on the interactions of those readers,K36 methylation was systematically studied in a defined cellular model. Contrasting prevailing models, K36me1, K36me2, and K36me3 were each found to contribute to distinct chromatin states. Monitoring the changing K36 methylation landscape upon depletion of the three methyltransferases Set2, NSD, and Ash1 revealed local, context-specific methylation signatures. Each methyltransferase governs K36 methylation in dedicated genomic regions, with minor overlaps. Set2 catalyzes K36me3 predominantly at transcriptionally active euchromatin. NSD places K36me2/3 at defined loci within pericentric heterochromatin and on weakly transcribed euchromatic genes. Ash1 deposits K36me1 at putative enhancers. The mapping of MSL3 and JASPer suggested that they bind K36me2 in addition to K36me3, which was confirmed by direct affinity measurement. This dual specificity attracts the readers to a broader range of chromosomal locations and increases the robustness of their actions. | Farmer, A. J., Katariya, R., Islam, S., Rayhan, M. S. A., Inlow, M. H., Ahmad, S. M., Schwab, K. R. (2025). trithorax is an essential regulator of cardiac Hox gene expression and anterior-posterior patterning of the Drosophila embryonic heart tube. Biol Open, 14(4) PubMed ID: 40172069
Summary: The precise regulation of transcription required for embryonic development is partially controlled by the actions of the Trithorax group (TrxG) and Polycomb group (PcG) proteins. The genes trithorax (trx), trithorax-related (trr), and SET domain containing 1 (Set1) encode COMPASS-like histone methyltransferases, a subgroup of TrxG proteins that impart H3K4 methylation modifications onto chromatin in order to activate and maintain transcription. This study identified the role of these genes in the development of the embryonic heart of the fruit fly Drosophila melanogaster. trx, trr, and Set1 independently ensure proper cardiac cell divisions. Additionally, trx regulation of collinear Hox expression is necessary for the anterior-posterior cardiac patterning of the linear heart tube. trx inactivation in Drosophila results in a remarkable homeotic transformation of the posterior heart-proper segment into an aorta-like fate due to the loss of posterior abdominal A expression. Furthermore, cardiac expression of Antennapedia, Ultrabithorax, and Abdominal B is also deregulated in trx mutants. Together, these data suggest that the COMPASS-like histone methyltransferases are essential developmental regulators of cardiogenesis, being necessary for both cardiac cell divisions and heart patterning. |
| Ostale, C. M., Azpiazu, N., Peropadre, A., Martin, M., Ruiz-Losada, M., Lopez-Varea, A., Viales, R. R., Girardot, C., Furlong, E. E. M., de Celis, J. F. (2025). A function of Spalt proteins in heterochromatin organization and maintenance of genomic DNA integrity. Development, 152(10) PubMed ID: 40326666
Summary: The conserved Spalt proteins regulate gene expression and cell fate choices during multicellular development, generally acting as transcriptional repressors in different gene regulatory networks. In addition to their roles as DNA sequence-specific transcription factors, Spalt proteins show a consistent localization to heterochromatic regions. Vertebrate Spalt-like proteins can act through the nucleosome remodeling and deacetylase complex to promote closing of open chromatin domains, but their activities also rely on interactions with DNA methyltransferases or with the lysine-specific histone demethylase LSD1, suggesting that they participate in multiple regulatory mechanisms. This study describes several consequences of loss of Spalt function in Drosophila cells, including changes in chromatin accessibility, generation of DNA damage, alterations in the localization of chromosomes within the nucleus in the salivary glands and misexpression of transposable elements. These effects are thought to be related to roles of Spalt proteins in the regulation of heterochromatin formation and chromatin organization. It is proposed that Drosophila Spalt proteins have two complementary functions, acting as sequence-specific transcriptional repressors on specific target genes and regulating more global gene silencing through the generation or maintenance of heterochromatic domains. | Mouginot, M., Hani, S., Cousin, P., Dorier, J., Ravera, A., Gambetta, M. C. (2025). A boundary-defining protein facilitates megabase-scale regulatory chromosomal loop formation in Drosophila neurons. Genes Dev, 39(11-12):706-726 PubMed ID: 40240144
Summary: Regulatory elements, such as enhancers and silencers, control transcription by establishing physical proximity to target gene promoters. Neurons in flies and mammals exhibit long-range three-dimensional genome contacts, proposed to connect genes with distal regulatory elements. However, the relevance of these contacts for neuronal gene transcription and the mechanisms underlying their specificity necessitate further investigation. This study precisely disrupt several long-range contacts in fly neurons, demonstrating their importance for megabase-range gene regulation was further revealed, and uncovering a hierarchical process in their formation. An essential role for the chromosomal boundary-forming protein Cp190 in anchoring many long-range contacts, highlighting a mechanistic interplay between boundary and loop formation. Finally, an unbiased proteomics-based method was developed to systematically identify factors required for specific long-range contacts. These findings underscore the essential role of architectural proteins such as Cp190 in cell type-specific genome organization in enabling specialized neuronal transcriptional programs. |
| Denaud, S., Sabaris, G., Di Stefano, M., Papadopoulos, G. L., Schuettengruber, B., Cavalli, G. (2025). Determining the functional relationship between epigenetic and physical chromatin domains in Drosophila. Genome Biol, 26(1):116 PubMed ID: 40340859
Summary: The tight correlation between topologically associating domains (TADs) and epigenetic domains in Drosophila suggests that the epigenome contributes to define TADs. However, it is still unknown whether histone modifications are essential for TAD formation and structure. By either deleting or shifting key regulatory elements needed to establish the epigenetic signature of Polycomb TADs, this study showed that the epigenome is not a major driving force for the establishment of TADs. On the other hand, physical domains have an important impact on the formation of epigenetic domains, as they can restrict the spreading of repressive histone marks and looping between cis-regulatory elements. | Melnikova, L. S., Balagurov, K. I., Georgiev, P. G., Golovnin, A. K. (2025). Identification of a Highly Conserved Region Critical for the Functionality of the Cp190 Protein in Drosophila melanogaster. Dokl Biochem Biophys, 521(1):178-182 PubMed ID: 40216711
Summary: The CP190 protein binds to both housekeeping gene promoters and insulator/boundary elements and plays a critical role in their activity. The aim of this work was to study the effect of deletions in highly conserved regions of the CP190 protein on its functionality. It was shown that deletion of the sequence from 664 to 700 aa leads to a lethal phenotype. Thus, a new region was identified in CP190 that plays an important role in the interaction of the CP190 protein with as yet unidentified partner proteins, stabilization of protein complexes formed by CP190, and their recruitment to chromatin. |
Monday February 23rd -Disease Models |
| Liang, Z., Murugappan, S. K., Li, Y., Lai, M. N., Qi, Y., Wang, Y., Chan, H. Y. E., Lee, M. M., Chan, M. K. (2025). Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease. Mol Ther, 33(7):3056-3072 PubMed ID: 40189878
Summary: Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogeneous intermediates. Previous work identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SUMO-interacting motif (SIM) interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomer formation, this study sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. SUMO1(15-55) is shown to selectively bind to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. Larval feeding of a designed His(10)-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate Parkinson's disease (PD)-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Thesee findings suggest that gene delivery of His(10)-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies. | Krzystek, T. J., Rathnayake, R., Zeng, J., Huang, J., Iacobucci, G., Yu, M. C., Gunawardena, S. (2025).. Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington's disease. Cell Death Dis, 16(1):328 PubMed ID: 40263294
Summary: Huntington's disease (HD)Huntingtin (HTT) gene leading to axonal degeneration and significant neuronal death. Despite evidence for a scaffolding role for HTT in membrane-related processes such as endocytosis, vesicle transport, and vesicle fusion, it remains unclear how polyQ-expansion alters membrane binding during these processes. Using quantitative Mass Spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons, significant changes were found in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes. Through a combination of in vitro kinase assays, Drosophila genetics, and pharmacological inhibitors, GSK3β and ERK1 were identified to phosphorylate HTT and that these events play distinct and opposing roles during HD with inhibition of GSK3β decreasing polyQ-mediated axonal transport defects and neuronal cell death, while inhibition of ERK enhancing these phenotypes. Together, this work proposes two novel pathways in which GSK3β phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction highlighting a highly druggable pathway for targeted therapeutics using already available small molecules. |
| Cao, Z., Zhang, C., Liu, L., Lei, H., Zhang, H., He, Y., Li, X., Xiang, Q., Wang, Y. F., Zhang, L., Chen, G. (2025). Microbiota-derived indole acetic acid extends lifespan through the AhR-Sirt2 pathway in Drosophila. mSystems, 10(5):e0166524 PubMed ID: 40197001
Summary: Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism have been shown to be highly associated with aging and age-related disorders. However, the underlying molecular mechanisms by which the AhR-mediated signaling pathway contributes to the aging process remain largely unknown. This study finds that aged Drosophila exhibits markedly reduced tryptophan metabolism leading to impaired AhR ligands, especially indole acetic acid (IAA), compared with their young controls. Supplementation with IAA, produced from Lactobacillus spp., dose-dependently extends the lifespan of Drosophila and improves healthy aging with resistance to starvation and oxidative stress. Mechanistically, activation of AhR by IAA markedly enhances Sirt2 activity by binding to its promoter, thereby inhibiting downstream TOR signaling and related fatty acid and amino acid metabolism. Both Ahr and Sirt2 mutant flies with IAA supplementation display a negligible lifespan extension, suggesting that AhR-mediated Sirt2 signaling contributes to lifespan extension in flies upon IAA supplementation. From the perspective of host metabolism, IAA supplementation significantly increases unsaturated fatty acids (UFAs) in aged flies, which are regarded to be beneficial for healthy status. These findings provide new insights into the physiological functions of AhR involved in the aging process by mediating Sirt2 signaling. | Buhl, E., Garg, S., Monaghan, M., Preston, A., Likeman, M., Dare, J., Evans, J., Taylor, L. S., Berry, I., Urankar, K., Spry, P. G. D., Williams, C., Taylor, R. W., Alston, C. L., Hodge, J. J. L., Majumdar, A. (2025). Infantile Cerebellar-Retinal Degeneration Associated With Novel ACO2 Variants: Clinical Features and Insights From a Drosophila Model. Clin Genet, PubMed ID: 40210596
Summary: Infantile Cerebellar-Retinal Degeneration (ICRD) is an autosomal recessive neuro-disability associated with hypotonia, seizures, optic atrophy, and retinal degeneration. Recessive variants of the mitochondrial aconitase gene (ACO2) are a known cause of ICRD. This study presents a paediatric male patient with ICRD, where whole genome sequencing of the family trio revealed segregating heterozygous variants of unknown significance in ACO2. At 4 months, he displayed generalised hypotonia, and by 6 years, visual electrophysiology indicated bilateral optic atrophy. Magnetic Resonance Imaging (MRI) at age seven confirmed optic nerve and cerebellar atrophy, and together with symptoms of developmental delay, align with ICRD. A Drosophila animal model was established to explore the impact of ACO2 loss- and gain-of-function. Manipulating the fly ortholog, mAcon1, through pan-neuronal knock-down or over-expression negatively affected longevity, locomotion, activity, whilst disrupting sleep and circadian rhythms. Mis-expression of mAcon1 in the eye led to impaired visual synaptic transmission and neurodegeneration. These experiments mirrored certain aspects of the human disease, providing a foundation for understanding its biological processes and pathogenic mechanisms, and offering insights into potential targets to screen for future treatments or preventive measures for ACO2-related ICRD. |
| He, G., Sun, J., Gu, Y., Zheng, Y., Wang, L., Sun, Y. (2025). Network analysis and in vivo experiments reveal the therapeutic mechanisms of total ginsenosides in a Drosophila model of ulcerative colitis. Front Pharmacol, 16:1556579 PubMed ID: 40201696
Summary: Gut homeostasis is critical for human health, ulcerative colitis (UC) can disrupt gut homeostasis and cause disease. Panax ginseng C.A. Meyer is a widely used traditional herbal medicine known for its anti-inflammatory, antioxidant, and immunomodulatory effects. However, the protective mechanisms of total ginsenosides (TG) in treating UC remain unclear. In this study, we employed Drosophila melanogaster as a model organism to investigate the protective effects of TG on dextran sulfate sodium (DSS)-induced intestinal injury. Our data showed that TG significantly improved survival rates in female flies, restored intestinal length, maintained intestinal barrier integrity, and alleviated oxidative stress. Additionally, TG may protect against intestinal damage by activating the PI3K/Akt signaling pathway and inhibiting the JAK/STAT signaling pathway. These findings suggest that TG alleviates UC symptoms through multi-target regulation, highlighting its potential for developing novel therapeutic strategies for UC. | Ham, S. J., Yoon, E., Lee, D. H., Kim, S., Yoo, H., Chung, J. (2025). Reciprocal rescue of Wolfram syndrome by two causative genes.EMBO Rep, 26(9):2459-2482 PubMed ID: 40181095
Summary: Wolfram syndrome (WS) is marked by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. The causative genes, WFS1 and CISD2, correspond to WS types 1 and 2, respectively. This study establishes their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP(3)R) activity, demonstrating their ability to restore reduced IP(3)R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, Drosophila WS models lacking dWFS1 or dCISDM exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of dWFS1 and dCISD in the flies alleviates their phenotypes. A peptide containing the CDGSH domain of CISD2, critical for its interaction with IP(3)R was engineered. Overexpression of the CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes. |
Thursday February 20th - Larval and adult neural development, structure and function |
| Gattuso, H. C., van Hassel, K. A., Freed, J. D., Nunez, K. M., de la Rea, B., May, C. E., Ermentrout, B., Victor, J. D., Nagel, K. I. (2025). Inhibitory control explains locomotor statistics in walking Drosophila. Proc Natl Acad Sci U S A, 122(16):e2407626122 PubMed ID: 40244663
Summary: In order to forage for food, many animals regulate not only specific limb movements but the statistics of locomotor behavior, switching between long-range dispersal and local search depending on resource availability. How premotor circuits regulate locomotor statistics is not clear. This study analyzed and modeled locomotor statistics and their modulation by attractive food odor in walking Drosophila. Food odor evokes three motor regimes in flies: baseline walking, upwind running during odor, and search behavior following odor loss. During search, this study found that flies adopt higher angular velocities and slower ground speeds and turn for longer periods in the same direction. Flies were further found to adopt periods of different mean ground speed and that these state changes influence the length of odor-evoked runs. We next developed a simple model of neural locomotor control that suggests that contralateral inhibition plays a key role in regulating the statistical features of locomotion. As the fly connectome predicts decussating inhibitory neurons in the (for information on premotor lateral accessory lobe neurons, go to Google AI and query premotor lateral accessory lobe neurons Drosophila) premotor lateral accessory lobe (LAL), genetic access was gained to a subset of these neurons, and their effects on behavior were tested. One population was identified whose activation induces all three signature of local search and that regulates angular velocity at odor offset. A second population, including a single LAL neuron pair, bidirectionally regulates ground speed. Together, this work develops a biologically plausible computational architecture that captures the statistical features of fly locomotion across behavioral states and identifies neural substrates of these computations. | Lee, W. P., Chiang, M. H., Chao, Y. P., Wang, Y. F., Chen, Y. L., Lin, Y. C., Jenq, S. Y., Lu, J. W., Fu, T. F., Liang, J. Y., Yang, K. C., Chang, L. Y., Wu, T., Wu, C. L. (2025). Dynamics of two distinct memory interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: 40244670
Summary: Forming and forgetting memories shape self-awareness and help facing future challenges. Therefore, understanding how memories are formed and how different memories interact in the brain is important. Previous studies have shown that thirsty flies sense humidity through ionotropic receptors, which help them locate water sources. This study showed that thirsty flies can be trained to associate specific odors with humidity to form a humidity memory that lasts for 30 min after association. Humidity memory formation requires the interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: Ir93a and es the interactions during water seeking in Drosophila. Proc Natl Acad Sci U S A, 122(16):e2422028122 PubMed ID: Ir40a ionotropic receptors, which are essential for environmental humidity sensing. Water memory takes precedence, leading to the forgetting of humidity memory by activating a small subset of dopaminergic neurons called protocerebral anterior medial (PAM)-&gamma4 (for information on NEURON neurons, go to Google AI and query protocerebral anterior medial (PAM)-&gamma4), that project to the restricted region of the mushroom body (MB) γ lobes. Adult-stage-specific silencing of Dop2R dopaminergic receptors in MB γ neurons prolongs humidity memory &gamma4; neural activity after odor/humidity association, suggesting its role in forgetting the humidity memory. These results suggest that overlapping neural circuits are responsible for the acquisition of water memory and forgetting humidity memory in thirsty flies. |
| Francis, J., Gibeily, C. R., Smith, W. V., Petropoulos, I. S., Anderson, M., Heitler, W. J., Prinz, A. A., Pulver, S. R. (2025). Inhibitory circuit motifs in Drosophila larvae generate motor program diversity and variability. PLoS Biol, 23(4):e3003094 PubMed ID: 40258087
Summary: How do neural networks generate and regulate diversity and variability in motor outputs with finite cellular components? This study examined this problem by exploring the role that inhibitory neuron motifs play in generating mixtures of motor programs in the segmentally organised Drosophila larval locomotor system. A computational model was developed that is constrained by experimental calcium imaging data. The model comprises single-compartment cells with a single voltage-gated calcium current, which are interconnected by graded excitatory and inhibitory synapses. Local excitatory and inhibitory neurons form conditional oscillators in each hemisegment. Surrounding architecture reflects key aspects of inter- and intrasegmental connectivity motifs identified in the literature. The model generates metachronal waves of activity that recapitulate key features of fictive forwards and backwards locomotion, as well as bilaterally asymmetric activity in anterior regions that represents fictive head sweeps. The statistics of inputs to competing command-like motifs, coupled with inhibitory motifs that detect activity across multiple segments generate network states that promote diversity in motor outputs, while at the same time preventing maladaptive overlap in motor programs. Overall, the model generates testable predictions for connectomics and physiological studies while providing a platform for uncovering how inhibitory circuit motifs underpin generation of diversity and variability in motor systems (Francis, 2025). | Martinez-Cordera, M., Sakai, T., Saitoe, M., Ueno, K. (2025). Comparative experience shapes sucrose preference through memory in Drosophila. Mol Brain, 18(1):32 PubMed ID: 40211246
Summary: \Selection of appropriate food is an ability that allows animals to make optimal foraging choices. However, the neural mechanisms that control this food selection remain unclear. The purpose of this study was to investigate the connection between memory and the feeding behavior of Drosophila melanogaster when two sucrose solutions with different concentrations are available. We placed flies into plates with 150 mM and 100 mM sucrose solutions and measured the preference for the 150 mM one. Flies preferred the 150 mM solution over the 100 mM when all 60 wells of the plate were filled with both solutions; this preference decreased when there were only 8 wells with food. Remarkably, prior exposure to a plate with all 60 wells filled with both solutions enhanced the preference for the 150 mM, even when there were only 8 wells with food. The memory-related gene rut and the dopamine D1 receptor on the mushroom body were required to enhance the preference after the prior exposure. These findings show that memory acquired through experiencing both solutions is stored in the mushroom body optimizing the food selection process (Martinez-Cordera. 2025. |
| Lu, W., Lee, B. S., Deng, H. X. Y., Lakonishok, M., Martin-Blanco, E., Gelfand, V. I. (2025). 'Mitotic' kinesin-5 is a dynamic brake for axonal growth in Drosophila. Development, 152(9) PubMed ID: 40223510
Summary: During neuronal development, microtubule reorganization shapes axons and dendrites, establishing the framework for efficient nervous system wiring. Previous work has demonstrated the role of kinesin-1 in driving microtubule sliding, which powers early axon outgrowth and regeneration in Drosophila melanogaster. This study reveals a crucial new role for kinesin-5, a mitotic motor, in modulating postmitotic neuron development. The Drosophila kinesin-5, Klp61F, is expressed in larval brain neurons, with high levels in ventral nerve cord (VNC) neurons. Knockdown of Klp61F in neurons leads to severe adult locomotion defects and lethality, primarily due to defects in VNC motor neurons. Klp61F depletion results in excessive microtubule penetration into the axon growth cone, causing significant axon growth defects in culture and in vivo. These defects are rescued by a chimeric human-Drosophila kinesin-5 motor, indicating a conserved role for kinesin-5 in neuronal development. Altogether, it is proposed that kinesin-5 acts as a brake on kinesin-1-driven microtubule sliding, ensuring proper axon pathfinding in growing neurons (Lu, 2025). | Flores-Valle, A., Vishniakou, I., Seelig, J. D. (2025). Dynamics of glia and neurons regulate homeostatic rest, sleep and feeding behavior in Drosophila. Nat Neurosci, 28(6):1226-1240 PubMed ID: 40259071
Summary: Homeostatic processes, including sleep, are critical for brain function. This study identified astrocyte-like glia (or astrocytes, AL) and ensheathing glia (EG), the two major classes of glia that arborize inside the brain, as brain-wide, locally acting homeostats for the short, naturally occurring rest and sleep bouts of Drosophila, and show that a subset of neurons in the fan-shaped body encodes feeding homeostasis.The metabolic gas carbon dioxide, changes in pH and behavioral activity all induce long-lasting calcium responses in EG and AL, and that calcium levels in both glia types show circadian modulation. The homeostatic dynamics of these glia can be modeled based on behavior. Additionally, local optogenetic activation of AL or EG is sufficient to induce rest. Together, these results suggest that glial calcium levels are homeostatic controllers of metabolic activity, thus establishing a link between metabolism, rest and sleep (Flores-Valle, 2025). |
Wednesday February 18th - Disease Models |
| Gonzalez-Gutierrez, A., Gaete, J., Esparza, A., Ibacache, A., Contreras, E. G., Sierralta, J. (2025). Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier. Glia, 73(8):1608-1626 PubMed ID: 40241296
Summary: Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood-brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In Drosophila melanogaster, carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of Drosophila monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. This study showed that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of Drosophila larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, this study identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. These findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB. | Zhang, X., Su, K. J., Banerjee, B., Eres, I., Hsu, Y. H., Crandall, C. J., Donaka, R., Han, Z., Jackson, R. D., Liu, H., Luo, Z., Mitchell, B. D., Qiu, C., Tian, Q., Shen, H., Tsai, M. J., Wiggins, K. L., Xu, H., Yau, M., Zhao, L. J., Zhang, X., Montasser, M. E., Kiel, D. P., Deng, H. W., Liu, C. T., Karasik, D. (2025). Multi-ancestry whole genome sequencing analysis of lean body mass. Genome Biol, 26(1):106 PubMed ID: 40296127
Summary: Lean body mass is a crucial physiological component of body composition. Although lean body mass has a high heritability, studies evaluating the genetic determinants of lean mass (LM) have to date been limited largely to genome-wide association studies (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, this study aimed to discover novel genetic variants associated with LM in population-based cohorts with multiple ancestries. The largest WGS-based meta-analysis of lean body mass to date is descrubed, encompassing 10,729 WGS samples from six TOPMed cohorts and the Louisiana Osteoporosis Study (LOS) cohort, measured with dual-energy X-ray absorptiometry. We identify seven genome-wide loci significantly associated with LM not reported by previous GWAS. These associations were partially reolicated in UK Biobank samples. In rare variant analysis, one novel protein-coding gene, DMAC1, was discovered associated with both whole-body LM and appendicular LM in females, and a long non-coding RNA gene linked to appendicular LM in males. Both genes exhibit notably high expression levels in skeletal muscle tissue. We investigate the functional roles of two novel lean-mass-related genes, EMP2 and SSUH2, in animal models. EMP2 deficiency in Drosophila leads to significantly reduced mobility without altering muscle tissue or body fat morphology, whereas an SSUH2 gene mutation in zebrafish stimulates muscle fiber growth. CONCLUSIONS: Our comprehensive analysis, encompassing a large-scale WGS meta-analysis and functional investigations, reveals novel genomic loci and genes associated with lean mass traits, shedding new insights into pathways influencing muscle metabolism and muscle mass regulation. |
| Guo, F. R., Wang, S. C., Liu, Y., Wang, S., Huang, J. M., Sun, H., He, L. F., Xie, Y., Qiao, S. T., Yang, F. X., Bass, C., Gao, C. F., Wu, S. F. (2025). CYP321F3 mediates metabolic resistance to methoxyfenozide in rice stem borer, Chilo suppressalis. Pestic Biochem Physiol, 210:106383 PubMed ID: 40262888
Summary: The development of insecticide resistance in insect populations is a major challenge to sustainable agriculture and food security worldwide. Methoxyfenozide, an insect growth regulator that acts as an agonist of 20-hydroxyecdysone (20E), has severely declined in its efficacy against the rice stem borer (Chilo suppressalis), a notorious pest of rice crops in East and Southeast Asia. To date, however, the genes involved in methoxyfenozide resistance in target pests remain unclear. A long-term (seven years from 2017 to 2023) and large geographical scale (8 provinces and 45 cities in China) resistance monitoring program were conducted for methoxyfenozide in C. suppressalis. Resistance was seen to arise rapidly in this species, with >100-fold resistance being detected in nearly all the field populations after 2018. Piperonyl butoxide (PBO), an inhibitor of cytochrome P450 enzymes (P450s), significantly increased the sensitivity of resistant strains of C. suppressalis to methoxyfenozide, implicating P450s in resistance. Six P450 genes: CYP321F3, CYP6CV5, CYP9A68, CYP6AB45, CYP324A12 and CYP6SN2 were identified as highly expressed in resistant C. suppressalis by transcriptome profiling. Of these, ectopic expression of CYP321F3 in Drosophila melanogaster resulted in a 7.0-fold increase in resistance to methoxyfenozide demonstrating its causal role in resistance. Collectively, these findings provide insight into the mechanisms mediating resistance to insect growth regulators and will inform the development of future pest and resistance management strategies. | Lei, C., Chen, Z., Hao, Y., Huang, W., Chu, T., Xiao, K., Zhang, C., Zhou, W., Li, C., Chen, X. (2025). Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila. Bioorg Med Chem, 124:118191 PubMed ID: 40245499
Summary: Protein O-GlcNAcylation plays a crucial role in Drosophila melanogaster development. Dysregulation of O-GlcNAc transferase (sxc/Ogt) and GlcNAcase (Oga) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in Drosophila. This study performed quantitative and site-specific profiling of O-GlcNAcylation in Drosophila by employing a chemoenzymatic labeling strategy. A total of 2196 unambiguous O-GlcNAcylation sites and 1308 O-GlcNAcylated proteins are identified. Quantitative analysis of O-GlcNAcylation in the head of Drosophila with sxc/Ogt knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in sxc/Ogt. RNAi Drosophila. Furthermore, quantitative analysis of O-GlcNAcylation under a high-sugar diet reveals altered O-GlcNAcylation of several proteins associated with obesity and neurological diseases, such as Hex-A and Ankyrin 2. This study not only establishes an effective method for large-scale identification of O-GlcNAcylation sites, but also provides a valuable resource for studying O-GlcNAc biology in Drosophila. |
| Abou Daya, F., Mandigo, T., Ober, L., Patel, D., Maher, M., Math, S., Tchio, C., Walker, J. A., Saxena, R., Melkani, G. C. (2025). Identifying links between cardiovascular disease and insomnia by modeling genes from a pleiotropic locus. Dis Model Mech, 18(5) PubMed ID: 40176577
Summary: Insomnia symptoms double the risk of cardiovascular disease (CVD), yet shared genetic pathways remain unclear. Genome-wide association studies identified a genetic locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1 and GIP) linked to insomnia and CVD. Drosophila models were used to perform tissue-specific RNA interference knockdowns of four conserved orthologs (ATPsynC, lsn, Bruce and Imp) in neurons and the heart. Neuronal-specific knockdown of ATPsynC, Imp and lsn impaired sleep quantity and quality. In contrast, cardiac knockdown of ATPsynC and lsn reduced cardiac function and lifespan, with lsn knockdown also causing cardiac dilation and myofibrillar disorganization. Cross-tissue effects were evident: neuronal Imp knockdown compromised cardiac function, whereas cardiac ATPsynC and lsn knockdown increased sleep fragmentation and inflammation (marked by Upd3 elevation in the heart or head). Overexpression of Upd3 in neurons impaired cardiac function, and its overexpression in the heart disrupted sleep. These findings reveal conserved genes mediating tissue-specific and cross-tissue interactions between sleep and cardiac function, providing novel insights into the genetic mechanisms linking insomnia and CVD through inflammation. | Geronazzo, J., Heimerl, A., Lindell, L., McCrimmon, S., Stormer, C., Horvai, B., Johnson, I. P., Peterson, T. M., Zuckerman, J., Scott, A. I., Course, M. M. (2025). Characterizing fatty acid oxidation genes in Drosophila. G3 (Bethesda), PubMed ID: 40519079
Summary: This study leveraged the power and tractability of Drosophila genetics to better understand the molecular mechanisms underlying a group of rare genetic diseases known as fatty acid oxidation disorders. CRISPR-Cas9 was used to generate mutations in six putative fatty acid oxidation genes in Drosophila, then analyze the phenotypes and acylcarnitine profiles of these flies. While Arc42 and CG4860 are both predicted orthologs of human ACADS, only Arc42 loss of function mirrors the acylcarnitine profile of ACADS loss of function. Acylcarnitine profiles also support a previous identification of Mcad as the likely ACADM ortholog, and reveal the deleterious effects of a single codon deletion in Mtp&alpha: (the predicted human HADHA ortholog). Finally, it was observed that loss of function in Etf-QO and in CG7834-predicted orthologs of human ETFDH and ETFB, respectively-is homozygous lethal in flies. Producing animal models like these will enable new approaches to studying fatty acid oxidation disease progression, symptomatic variability, and therapeutic intervention. |
Tuesday February 17th - Disease Models |
| He, L., Zhang, Y., Li, J., Chen, D., Yue, S., Liu, Y., Guo, Y., Wang, Y., Xiu, M., He, J. (2025). Dunhuang Dabupi Decoction and its active components alleviate ulcerative colitis by activating glutathione metabolism and inhibiting JAK-STAT pathway in Drosophila and mice. J Ethnopharmacol, 346:119717 PubMed ID: 40164365
Summary: Dabupi Decoction (DBPD) originates from the ancient Dunhuang medical literature "Fu Xing Jue Visceral to Drug law legend" for more than 1000 years, which has been extensively employed to treat various diseases related to the spleen and stomach. However, limited studies focus on the mechanism of DBPD against ulcerative colitis (UC). The beneficial effect and mechanism of DBPD against UC were detected by adopting both Drosophila melanogaster and C57BL/6J mouse models. The protective effect of DBPD against DSS-induced intestinal damage in flies was investigated In mice, Liquid chromatography-mass spectrometry (LC-MS) and phenotype experiments in UC flies were utilized to identify the bioactive components of DBPD against UC. Oral administration of DBPD remarkably alleviated DSS-induced body damage in flies by improving survival rate, locomotion, and excretion. It also remarkably rescued intestinal morphological damage, repaired acid-base homeostatic imbalance, inhibited intestinal epithelial cells (IECs) death and excessive proliferation of intestinal stem cells (ISCs), and improved ultrastructural damage of IECs in flies treated with DSS. Consistently, DBPD attenuated colitis symptoms, alleviated intestinal histopathological damage, and restored the expression of inflammatory factors in DSS-induced UC mice. As suggested by an integration of transcriptome data with molecular biology experiments, DBPD not only dramatically alleviated oxidative damage by activating the glutathione metabolic pathway, but also lowered inflammatory reaction by inhibiting the JAK-STAT pathway. Additionally, four compounds of DBPD, rhein acid, isoquercitrin, curcumin, and zeaxanthin were identified to alleviate the DSS-induced intestinal injury. CONCLUSION: DBPD demonstrate immense potential for intestinal injury predominantly by activating the glutathione metabolic pathway to alleviate oxidative damage, and inhibiting the JAK-STAT pathway to mitigate inflammatory response. Rhein acid, isoquercitrin, curcumin, and zeaxanthin were the bioactive compounds of DBPD against UC. | Heckmann, M., Sadova, N., Sandner, G., Neuhauser, C., Blank-Landeshammer, B., Schwarzinger, B., Konig, A., Liang, M., Spitzer, M., Weghuber, J., Stadlbauer, V. (2025). Herbal extract fermented with inherent microbiota improves intestinal health by exerting antioxidant and anti-inflammatory effects in vitro and in vivo. J Anim Sci Biotechnol, 16(1):52 PubMed ID: 40188119
Summary: Maintaining intestinal health is crucial for the overall well-being and productivity of livestock, as it impacts nutrient absorption, immune function, and disease resistance. Oxidative stress and inflammation are key threats to intestinal integrity. This study explored the antioxidant, anti-inflammatory, and barrier-strengthening properties of a fermented plant macerate (FPM) derived from 45 local herbs, using a specifically developed fermentation process utilizing the plants' inherent microbiota to enhance bioactivity and sustainability. In vitro experiments with IPEC-J2 cells showed that FPM significantly reduced intracellular reactive oxygen species (ROS) levels, improved barrier integrity, and enhanced cell migration under stress. Similar antioxidant effects were observed in THP-1 macrophages, where FPM reduced ROS production and modulated inflammatory responses by decreasing pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α), monokine induced by gamma interferon (MIG), interferon-inducible T cell alpha chemoattractant (I-TAC), macrophage inflammatory proteins (MIP)-1α and -1β] and increasing anti-inflammatory interleukin (IL)-10 levels. Mechanistic studies with HEK-Blue reporter cell lines revealed that FPM inhibited nuclear factor kappa B (NF-kappaB) activation via a FBgn0032095">toll-like receptor (TLR)4-independent pathway. In vivo, FPM significantly reduced ROS levels in Drosophila melanogaster and improved activity and LT(50) values in Caenorhabditis elegans under oxidative stress, although it did not affect intestinal barrier integrity in these models. The findings indicate that FPM shows promising application as a functional feed supplement for improving intestinal health in livestock by mitigating oxidative stress and inflammation. Further studies, including livestock feeding trials, are recommended to validate these results. |
| Justice, J. L., Greco, T. M., Hutton, J. E., Reed, T. J., Mair, M. L., Botas, J., Cristea, I. M. (2025). Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures. Mol Syst Biol, 21(5):492-522 PubMed ID: 40169779
Summary: Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. This aspect was investigated by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. An HTT association was established with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, this study found HTT modulates the subcellular localization and assembly of the Mediator. striatal enriched and functional interactions were demonstrated with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology. | Huang, Y., Xiang, Z., Xiang, Y., Pan, H., He, M., Guo, Z., Kanca, O., Liu, C., Zhang, Z., Zhan, H., Wang, Y., Bai, Q. R., Bellen, H. J., Wang, H., Bian, S., Mao, X. (2025). Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome. J Genet Genomics, PubMed ID: 40254158
Summary: Mediator Complex Subunit 16 (MED16, MIM: 604062) is a member of the Mediator complex, which controls many aspects of transcriptional activity in all eukaryotes. This study reports two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing. The affected individuals present with global developmental delay, intellectual disability, and dysmorphisms. To assess the pathogenicity of the variants, functional studies are performed in Drosophila and patient-derived cells. The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system (CNS). Loss of med16 leads to a reduction in eclosion and lifespan, as well as impaired synaptic transmission. In neurons differentiated from the patient-derived induced pluripotent stem cells (iPSCs), the neurite outgrowth is impaired and rescued by expression of exogenous MED16. The patient-associated variants behave as loss-of-function (LoF) alleles in flies and iPSCs. Additionally, the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls. In summary, these findings support that MED16 is important for appropriate development and function, and that biallelic MED16 variants cause a neurodevelopmental disease. |
| Kirio, K., Patop, I. L., Anduaga, A. M., Harris, J., Pamudurti, N., Su, T. N., Martel, C., Kadener, S. (2025). Circular RNAs exhibit exceptional stability in the aging brain and serve as reliable age and experience indicators. ell Rep, 44(4):115485 PubMed ID: 40184256
Summary: Circular RNAs (circRNAs) increase in the brain with age across various animal systems. To elucidate the reasons behind this phenomenon, this study profile circRNAs from fly heads at six time points throughout their lifespan. The results reveal a linear increase in circRNA levels with age, independent of changes in mRNA levels, overall transcription, intron retention, or host gene splicing, demonstrating that the age-related accumulation is due to high stability rather than increased biogenesis. This remarkable stability suggests that circRNAs can serve as markers of environmental experience. Indeed, flies exposed to a 10-day regimen at 29°deg;C exhibit higher levels of specific circRNAs even 6 weeks after returning to standard conditions, indicating that circRNAs can reveal past environmental stimuli. Moreover, half-life measurements show circRNA stability exceeding 20 days, with some displaying virtually no degradation. These findings underscore the remarkable stability of circRNAs in vivo and their potential as markers for stress and life experiences. | Keesey, I. W., Doll, G., Chakraborty, S. D., Baschwitz, A., Lemoine, M., Kaltenpoth, M., Svatos, A., Sachse, S., Knaden, M., Hansson, B. S. (2025). Neuroecology of alcohol risk and reward: Methanol boosts pheromones and courtship success in Drosophila melanogaster. Sci Adv, 11(14):eadi9683 PubMed ID: 40173238
Summary: Attraction of Drosophila melanogaster toward by-products of alcoholic fermentation, especially ethanol, has been extensively studied. Previous research has provided several interpretations of this attraction, including potential drug abuse, or a self-medicating coping strategy after mate rejection. We posit that the ecologically adaptive value of alcohol attraction has not been fully explored. Here, the authors assert a simple yet vital biological rationale for this alcohol preference. Flies display attraction to fruits rich in alcohol, specifically ethanol and methanol, where contact results in a rapid amplification. Olfactory sensory neurons that detect these alcohols, where roles were revealed in both attraction and aversion, and show that valence is balanced around alcohol concentration. Moreover,methanol can be deadly, and adult flies must therefore accurately weigh the trade-off between benefits and costs for exposure within their naturally fermented and alcohol-rich environments. |
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