Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability

Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability | 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 Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability Ryan Gray, Valeria Aceves, Ziyi Xu, Cheng-Hai Zhang, Jongkil Kim, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9271349/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 Adolescent idiopathic scoliosis (AIS) is the most common spinal disorder in children and is best understood as a complex polygenic condition. Genome-wide association studies (GWAS) have identified several AIS risk loci, including regions near ADGRG6 and SOX9, yet the functional mechanisms underlying AIS heritability remain poorly defined. Here, we use spatial transcriptomics to characterize altered gene expression in the spine of a conditional Adgrg6 mutant mouse model of AIS (Adgrg6-cKO), revealing reduced expression of Sox9 and several components of extracellular matrix organization in the intervertebral disc. We further show that SOX9 occupies regions of open chromatin within the Adgrg6 locus in cells isolated from the mouse intervertebral disc. Finally, we demonstrate a strong genetic interaction between Adgrg6-cKO and a hypomorphic Sox9 allele that increases both the penetrance and severity of AIS-like pathology in mice. Collectively, these findings support a self-reinforcing feedforward regulatory circuit, where Adgrg6 and Sox9 are co-regulated to maintain extracellular matrix gene expression in the annulus fibrosus and paraspinal tissues. These findings provide mechanistic insight into the functional significance of AIS-associated GWAS loci near ADGRG6 and SOX9 and establish combined Adgrg6–Sox9 insufficiency as a tractable model of polygenic scoliosis susceptibility. Biological sciences/Developmental biology/Disease model Biological sciences/Genetics/Gene expression Full Text Additional Declarations There is NO Competing Interest. 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. 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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-9271349","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":618445230,"identity":"27c4b39e-e478-4f39-b08f-8eafa033ad4a","order_by":0,"name":"Ryan 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Genome-wide association studies (GWAS) have identified several AIS risk loci, including regions near ADGRG6 and SOX9, yet the functional mechanisms underlying AIS heritability remain poorly defined. Here, we use spatial transcriptomics to characterize altered gene expression in the spine of a conditional Adgrg6 mutant mouse model of AIS (Adgrg6-cKO), revealing reduced expression of Sox9 and several components of extracellular matrix organization in the intervertebral disc. We further show that SOX9 occupies regions of open chromatin within the Adgrg6 locus in cells isolated from the mouse intervertebral disc. Finally, we demonstrate a strong genetic interaction between Adgrg6-cKO and a hypomorphic Sox9 allele that increases both the penetrance and severity of AIS-like pathology in mice. Collectively, these findings support a self-reinforcing feedforward regulatory circuit, where Adgrg6 and Sox9 are co-regulated to maintain extracellular matrix gene expression in the annulus fibrosus and paraspinal tissues. These findings provide mechanistic insight into the functional significance of AIS-associated GWAS loci near ADGRG6 and SOX9 and establish combined Adgrg6–Sox9 insufficiency as a tractable model of polygenic scoliosis susceptibility.","manuscriptTitle":"Genetic interaction between Adgrg6 and Sox9 reveals a feedforward mechanism for postnatal spinal stability","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-08 11:34:59","doi":"10.21203/rs.3.rs-9271349/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"49a7a4d0-6a74-4f84-8cb3-0931ad3f0d0f","owner":[],"postedDate":"April 8th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Reject after peer review","date":"2026-04-30T16:42:40+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65808944,"name":"Biological sciences/Developmental biology/Disease model"},{"id":65808945,"name":"Biological sciences/Genetics/Gene expression"}],"tags":[],"updatedAt":"2026-04-30T16:46:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-08 11:34:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9271349","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9271349","identity":"rs-9271349","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}