miR-34 regulates stress-induced depression-like state through the WDR26 ortholog melancholy in Drosophila

miR-34 regulates stress-induced depression-like state through the WDR26 ortholog melancholy in Drosophila | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article miR-34 regulates stress-induced depression-like state through the WDR26 ortholog melancholy in Drosophila Shreyasi Mitra, Amit Kumar, Aman Gill, Majid Ali, Aman Bashar, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9339604/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Major depressive disorder (MDD) is a complex and recurrent neuropsychiatric disorder with poorly understood molecular underpinnings. Psychosocial stress is a major environmental risk factor, yet the mechanisms linking stress exposure to behavioral outcomes remain unclear. MicroRNAs (miRNAs) have emerged as key regulators linking environmental stress to changes in gene expression in mood disorders. Here, using stress-induced rodent and Drosophila models, we identify the conserved, brain-enriched miRNA, miR-34, as a critical mediator of stress responses. Our expression analysis revealed significant downregulation of miR-34 in brain tissues from stress-induced depressed rodent and fruit fly models. We showed that this stress-induced downregulation of miR-34 is due to the upregulation of its transcriptional inhibitor Broad. Loss of miR-34 in flies induces depression-like behavior even in the absence of stress, whereas its overexpression in serotonin-sensing neurons confers resilience. We identify a conserved regulatory axis between miR-34 and CG7611, encoding the WDR26 ortholog Melancholy (Mel). Reducing mel levels mimics miR-34 overexpression, while its upregulation induces depression-like phenotypes. Proteomic analysis shows that mel overexpression recapitulates a stress-like state, characterized by downregulation of cytoskeletal, nuclear pore, chromatin, and transcriptional proteins, alongside upregulation of mitochondrial, metabolic, and detoxification pathways. These coordinated changes indicate a shift toward a low-activity, neuroprotective neuronal state driven by nuclear reprogramming and metabolic adaptation. Together, our findings reveal a conserved, adult-specific role for the CTLH complex in stress responses and establish miR-34 as a dosage-sensitive regulator of depression-like states. Biological sciences/Psychology/Human behaviour Biological sciences/Genetics/Behavioural genetics MicroRNAs depression miR-34 stress behaviour Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS6.xlsx Table S6 TableS4.xlsx Table S4 TableS5.xlsx Table S5 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9339604","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":618897434,"identity":"3333f8f8-ead0-4922-94c5-aa7d108c99b7","order_by":0,"name":"Shreyasi Mitra","email":"","orcid":"","institution":"RNA Biology Laboratory, Department of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence, Uttar Pradesh-201314, India","correspondingAuthor":false,"prefix":"","firstName":"Shreyasi","middleName":"","lastName":"Mitra","suffix":""},{"id":618897435,"identity":"33d0f401-e384-4399-a667-06f95602600b","order_by":1,"name":"Amit 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Psychosocial stress is a major environmental risk factor, yet the mechanisms linking stress exposure to behavioral outcomes remain unclear. MicroRNAs (miRNAs) have emerged as key regulators linking environmental stress to changes in gene expression in mood disorders. Here, using stress-induced rodent and Drosophila models, we identify the conserved, brain-enriched miRNA, miR-34, as a critical mediator of stress responses. Our expression analysis revealed significant downregulation of miR-34 in brain tissues from stress-induced depressed rodent and fruit fly models. We showed that this stress-induced downregulation of miR-34 is due to the upregulation of its transcriptional inhibitor Broad. Loss of miR-34 in flies induces depression-like behavior even in the absence of stress, whereas its overexpression in serotonin-sensing neurons confers resilience. We identify a conserved regulatory axis between miR-34 and CG7611, encoding the WDR26 ortholog Melancholy (Mel). 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