Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance

Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance | 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 Biological Sciences - Article Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance Takeshi Yagi, Ryuon Higuchi, Masaki Tatara, Satoko Horino, Shota Katori, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6625601/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Mar, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Animal models of human disease syndromes are useful for elucidating disease causes and developing treatments. The protocadherin γC4 (Pcdh-γC4) among the 22 isoforms encoded by the protocadherin-γ (Pcdh-γ) gene cluster causes a human neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disorder. Here, we successfully established a useful mouse model of human Pcdh-γC4 neurodevelopmental syndrome, which exhibited motor disfunctions, seizures, brain size reduction, massive neuronal apoptosis and impaired dendritic development of Purkinje cells. At the same times, we generated Pcdh-γC4 only mice that express only full-length Pcdh-γC4 and truncated forms of the other 21 Pcdh-γ isoforms by using a two-step CRISPR/Cas9-based genome editing strategy, DOMINO (Double Mutation Inducing Open reading frame switch). These mice were viable and fertile, unlike Pcdh-γ cluster knockout mice. Biochemical analyses revealed that Pcdh-γC4 significantly regulates phosphorylation of FAK and PYK2, implicating its γ-constant domain in intracellular signaling. Furthermore, we found that Pcdh-γC4 is sufficient to restore normal dendritic self-avoidance of Purkinje cells observed in Pcdh-γ full-cluster knockouts. These findings demonstrate that Pcdh-γC4 is both necessary and sufficient for neuronal survival, dendritic patterning, and signaling, highlighting it as a functionally dominant isoform within the Pcdh-γ gene cluster. Biological sciences/Neuroscience/Genetics of the nervous system Biological sciences/Neuroscience/Molecular neuroscience Full Text Additional Declarations There is NO Competing Interest. In our submitted manuscript, all experiments were approved by the Animal Experiment Committees of the Osaka University and National Institute for Physiological Sciences. Supplementary Files ExtendedDataVideo1.mov Gross phenotype of Pcdh-γWT and Pcdh-γ∆C4 at P0 ExtendedDataVideo2.mov Gross phenotype of Pcdh-γC4only at P0 ExtendedDataVideo3.mov Typical gait of survived adult Pcdh-γ∆C4 mice. The survived Pcdh-γ∆C4 fell from scaffolds and exhibited epileptic-like behavior. ExtendedDataVideo4.mov Gross phenotype of Pcdh-γC4-N∆79 at P0 ExtendedDataVideo5.mov Tetbow labeled Purkinje cells of Pcdh-γWT, Pcdh-γ∆C4, and Pcdh-γC4only at P28. ExtendedDataVideo6.mov Immunostaining of L7 promoter driven PA-tagged Pcdh-γC4 overexpression in PV-cre; Pcdh-γflox/flox Purkinje cells. Cite Share Download PDF Status: Published Journal Publication published 07 Mar, 2026 Read the published version in Communications Biology → 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. 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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-6625601","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":454400243,"identity":"7e0ba352-2019-4808-9bd1-181050eed8a8","order_by":0,"name":"Takeshi 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The protocadherin γC4 (Pcdh-γC4) among the 22 isoforms encoded by the protocadherin-γ (Pcdh-γ) gene cluster causes a human neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disorder. Here, we successfully established a useful mouse model of human Pcdh-γC4 neurodevelopmental syndrome, which exhibited motor disfunctions, seizures, brain size reduction, massive neuronal apoptosis and impaired dendritic development of Purkinje cells. At the same times, we generated Pcdh-γC4 only mice that express only full-length Pcdh-γC4 and truncated forms of the other 21 Pcdh-γ isoforms by using a two-step CRISPR/Cas9-based genome editing strategy, DOMINO (Double Mutation Inducing Open reading frame switch). These mice were viable and fertile, unlike Pcdh-γ cluster knockout mice. Biochemical analyses revealed that Pcdh-γC4 significantly regulates phosphorylation of FAK and PYK2, implicating its γ-constant domain in intracellular signaling. Furthermore, we found that Pcdh-γC4 is sufficient to restore normal dendritic self-avoidance of Purkinje cells observed in Pcdh-γ full-cluster knockouts. These findings demonstrate that Pcdh-γC4 is both necessary and sufficient for neuronal survival, dendritic patterning, and signaling, highlighting it as a functionally dominant isoform within the Pcdh-γ gene cluster.","manuscriptTitle":"Protocadherin γC4 regulates neuronal survival and dendritic self-avoidance","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-04 14:53:39","doi":"10.21203/rs.3.rs-6625601/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b2a9b489-24eb-4442-854c-a9ca86818091","owner":[],"postedDate":"June 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":48320079,"name":"Biological sciences/Neuroscience/Genetics of the nervous system"},{"id":48320080,"name":"Biological sciences/Neuroscience/Molecular neuroscience"}],"tags":[],"updatedAt":"2026-04-21T07:08:03+00:00","versionOfRecord":{"articleIdentity":"rs-6625601","link":"https://doi.org/10.1038/s42003-026-09778-6","journal":{"identity":"communications-biology","isVorOnly":false,"title":"Communications Biology"},"publishedOn":"2026-03-07 05:00:00","publishedOnDateReadable":"March 7th, 2026"},"versionCreatedAt":"2025-06-04 14:53:39","video":"","vorDoi":"10.1038/s42003-026-09778-6","vorDoiUrl":"https://doi.org/10.1038/s42003-026-09778-6","workflowStages":[]},"version":"v1","identity":"rs-6625601","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6625601","identity":"rs-6625601","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}