The orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells

The orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells | 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 Research Article The orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells Matthias Weider, Magdalena C. Wagner, Theresa Schmid, Sebastian Gehlen-Breitbach, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7661291/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Orofacial clefts represent the most prevalent congenital anomalies affecting the craniofacial region. They can be evoked by a disturbed development of either oral epithelium or cranial neural crest-derived mesenchyme, or by disruptions of their interplay. IRF6 is a well-known risk gene associated with orofacial clefts. Its expression in the oral epithelium depends on the transcription factor AP-2α, encoded by TFAP2A. We here show by immunofluorescence on mouse embryonic sections and by mining of single cell RNA-seq data that IRF6 is also expressed in cranial neural crest-derived tissue in mice and humans, together with TFAP2A and SOX9. The IRF6 enhancer MCS-9.7 can be activated by the transcription factor SOX9, mutations of which cause Pierre Robin sequence, a craniofacial anomaly that includes cleft palate. This SOX9-dependent activation is influenced by the single nucleotide variant rs76145088 that is associated with orofacial clefting. Inactivation of Sox9 in a murine neural crest cell line by CRISPR/Cas9 results in loss of Irf6 expression. We conclude that dysregulation of the SOX9–IRF6 axis in cranial neural crest cells could be relevant for the pathogenesis of orofacial clefting. palate development craniofacial development cleft lip cleft palate transcriptional regulation craniofacial developmental biology single cell RNA-seq single cell transcriptomics cell-cell communication Figures Figure 1 Figure 2 Figure 3 Full Text Supplementary Files FigS1.jpg SupplementaryTables.xlsx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major Revisions Needed 05 Nov, 2025 Reviewers agreed at journal 07 Oct, 2025 Reviewers invited by journal 07 Oct, 2025 Editor assigned by journal 26 Sep, 2025 First submitted to journal 22 Sep, 2025 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-7661291","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":525802469,"identity":"3076c159-d16b-462e-9fa9-69287aa1c3ed","order_by":0,"name":"Matthias Weider","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYJACZgYDCOMADwODHHsDkMWDXwNjM7IWY54DRGmBAaDKxB5CWnTbzx9/XFBgZ88gkXzwwJuKe+k97GcMGN5U4NZidiaZsXmGQXJig0RawsE5Z4pze3hyDBjnnMGj5QBQC48BcwKDdI7BYd62hNz9DDkGzLxteLScfwzSUm/PIJ3/4TDvv4R0Hv43QC3/8Gi5AbblMGODdA7DYd6GhAQeCZAtDfi0PDaczWNwPLFN/pnBwTnHEgx7JJ4VABn4HJb44DPPn2p7fp7Djz+8qUmQ5+FP3vjgTQ1uLXDAhsw5QISGUTAKRsEoGAV4AAASCVAAEN/4+AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-4820-6158","institution":"Universitätsklinikum Erlangen Zahnklinik 3 Kieferorthopädie: Universitatsklinikum Erlangen Zahnklinik 3 Kieferorthopadie","correspondingAuthor":true,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Weider","suffix":""},{"id":525802470,"identity":"10a2706c-fdfe-440b-9d47-84f83d58f1cc","order_by":1,"name":"Magdalena C. Wagner","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Zahnklinik 3 Kieferorthopädie: Universitatsklinikum Erlangen Zahnklinik 3 Kieferorthopadie","correspondingAuthor":false,"prefix":"","firstName":"Magdalena","middleName":"C.","lastName":"Wagner","suffix":""},{"id":525802471,"identity":"cf848e34-0381-4e18-99ee-8e44f8a0c809","order_by":2,"name":"Theresa Schmid","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Zahnklinik 3 Kieferorthopädie: Universitatsklinikum Erlangen Zahnklinik 3 Kieferorthopadie","correspondingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"Schmid","suffix":""},{"id":525802472,"identity":"808b12d0-68f4-4ce9-8356-e150b175b6bd","order_by":3,"name":"Sebastian Gehlen-Breitbach","email":"","orcid":"","institution":"Friedrich-Alexander-Universitat Erlangen-Nurnberg, Lehrstuhl für Biochemie und Pathobiochemie","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Gehlen-Breitbach","suffix":""},{"id":525802473,"identity":"d0797e13-d95a-45af-866f-7e6737b47cae","order_by":4,"name":"Gabriele Rodrian","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Zahnklinik 3 Kieferorthopädie: Universitatsklinikum Erlangen Zahnklinik 3 Kieferorthopadie","correspondingAuthor":false,"prefix":"","firstName":"Gabriele","middleName":"","lastName":"Rodrian","suffix":""},{"id":525802474,"identity":"8d80db16-40d6-49f8-8b4b-e280c1dc35a5","order_by":5,"name":"Nicolai Peschel","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Kinder- und Jugendklinik: Universitatsklinikum Erlangen Kinder- und Jugendklinik","correspondingAuthor":false,"prefix":"","firstName":"Nicolai","middleName":"","lastName":"Peschel","suffix":""},{"id":525802475,"identity":"42560d8a-e5bb-4d39-955c-722d9aae84fb","order_by":6,"name":"Holm Schneider","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Kinder- und Jugendklinik: Universitatsklinikum Erlangen Kinder- und Jugendklinik","correspondingAuthor":false,"prefix":"","firstName":"Holm","middleName":"","lastName":"Schneider","suffix":""},{"id":525802476,"identity":"388d3194-d2f3-4f7e-b1a6-55d015d8cbaa","order_by":7,"name":"Kerstin U. Ludwig","email":"","orcid":"","institution":"Universität Bonn, Institut für Humangenetik","correspondingAuthor":false,"prefix":"","firstName":"Kerstin","middleName":"U.","lastName":"Ludwig","suffix":""},{"id":525802477,"identity":"69232618-d53c-4d4c-8e87-4de1870ea2c6","order_by":8,"name":"Michael Wegner","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg, Lehrstuhl für Biochemie und Pathobiochmie","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Wegner","suffix":""},{"id":525802478,"identity":"19950d16-b9c1-48f8-8efe-6f2586d99c84","order_by":9,"name":"Lina Gölz","email":"","orcid":"","institution":"Universitätsklinikum Erlangen Zahnklinik 3 Kieferorthopädie: Universitatsklinikum Erlangen Zahnklinik 3 Kieferorthopadie","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Gölz","suffix":""}],"badges":[],"createdAt":"2025-09-19 22:04:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7661291/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7661291/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93894415,"identity":"571afcb0-2908-4dd2-8b79-d0acef550982","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"jpg","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1188509,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/24b3f7e13b65f8fa2797484e.jpg"},{"id":93894945,"identity":"c1b6563e-2511-435c-a568-eb9b525d4286","added_by":"auto","created_at":"2025-10-20 02:54:30","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":409717,"visible":true,"origin":"","legend":"","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/7112d0639af235f35cb949ed.jpg"},{"id":93895189,"identity":"55d2e2d8-6d41-47b9-b8d3-2245e3b5f7a0","added_by":"auto","created_at":"2025-10-20 03:02:30","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":499012,"visible":true,"origin":"","legend":"","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/5b73112eded39c0f5c6918d9.jpg"},{"id":93894420,"identity":"004340be-7a8c-4c09-a317-accdbd666a87","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14441,"visible":true,"origin":"","legend":"","description":"","filename":"jmmeJMMED2500780.xml","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/add436d0c5f16ee078581f36.xml"},{"id":93894947,"identity":"8986aa01-e0ae-451f-87aa-e668c38eb711","added_by":"auto","created_at":"2025-10-20 02:54:30","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1224,"visible":true,"origin":"","legend":"","description":"","filename":"JMMED250078016733.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/620327db21dec05710777d3d.xml"},{"id":93894949,"identity":"e8a5934a-68c0-4671-afc6-3c9738aee1c1","added_by":"auto","created_at":"2025-10-20 02:54:30","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":872,"visible":true,"origin":"","legend":"","description":"","filename":"JMMED2500780Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/55ac10d1d222db13cc2f2922.xml"},{"id":93894417,"identity":"50822d41-9956-46ac-84ce-eaca7e2fdd43","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1188509,"visible":true,"origin":"","legend":"\u003cp\u003eIrf6 is co-expressed with Sox9 and Tfap2a in cranial neural crest-derived mesenchymal tissue. (A) Immunofluorescent staining of Irf6 protein (red) neural crest-derived tissue of murine pharyngeal arches labelled by Wnt1::Cre-activated YFP-expression (green) from the Rosa26-stopflox-YFP locus at embryonic days E9.5, E10.5 and E11.5. Cell nuclei are counterstained with Hoechst 33342 (blue). (B,C) Co-localization of Irf6 (red) with Sox9 (green, B) and Tfap2a (green, C). Cell nuclei are counterstained with Hoechst 33342 (blue). (D) Uniform Manifold Approximation and Projection plots (UMAP) of all cell types from human CS17 and murine E12.5 craniofacial tissue calculated with scRNA-seq data from Yankee et al. 2023 [35]. (E) UMAP colored by normalized gene expression of IRF6 on the dataset from (D). (F) UMAP of mesenchymal cells from human CS17 (CS17) and murine E12.5 (E12-5) craniofacial tissue calculated with scRNA-seq data from Yankee et al. 2023 [35]. (G) UMAP colored by normalized gene expression of IRF6 on the dataset from (F). (H,I) UMAPs colored by normalized gene expression of IRF6 (red) and SOX9 (J, blue) or TFAP2A (K, blue) on the dataset from (F). Size bars: 50 μm.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/2aae9d9f6f4a432dc50c90b5.jpg"},{"id":93894946,"identity":"6898b0b4-f39a-40ca-bac5-02b9fccc91da","added_by":"auto","created_at":"2025-10-20 02:54:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":409717,"visible":true,"origin":"","legend":"\u003cp\u003eThe SOX9-dependent activation of the IRF6 enhancer MCS-9.7 is influenced by the orofacial cleft risk SNV rs76145088. (A) Schematic representation of IRF6 and MCS-9.7 and zoom-in depicting nucleotide sequence with the TFAP2A binding site around rs64961 and the putative SOX binding site spanning rs76145088. (B) Sequences of putative SOX binding site around rs76145088 (in boldface) with ancestral allele (turquoise, upper line) and derived allele (blue, lower line) aligned to position weight matrix for SOX9 monomeric binding from JASPAR database (JASPAR release 2022, matrix ID MA0077.1). (C,D) Luciferase assays of MCS-9.7 containing ancestral (petrol bars) or derived allele (blue bars) of rs76145088 in Neuro-2A cells with effector plasmids expressing TFAP2A (+ in B) or SOX9 (+ in C) or empty control vectors (-) with luciferase units of controls arbitrarily set to 1. (E) Luciferase assay of MCS-9.7 with varying amounts of SOX9 effector plasmid. Statistics were performed with t-tests between effectors and controls, or between the different alleles, and with one-way ANOVA within each series (either ancestral or derived allele) containing samples with increasing SOX9 amounts. Graph bars represent arithmetic means ± SEM (N = 3). Asterisks depict statistically significant differences within experimental series containing a specific allelic variant of MCS-9.7, hashtags depict statistically significant differences between allelic variants. *0.01 ≤ p \u0026lt; 0.05, **0.001 ≤ p \u0026lt; 0.01, ***p \u0026lt; 0.001; #0.01 ≤ p \u0026lt; 0.05, ##0.001 ≤ p \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/9f1ba6eeae992c0a93bc2f2c.jpg"},{"id":93894421,"identity":"36c5df5a-d838-4b56-b9c0-259503cb4ed0","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":499012,"visible":true,"origin":"","legend":"\u003cp\u003eExpression of Irf6 in O9-1 cranial neural crest cells depends on Sox9. (A) Schematic representation of Sox9 protein and genomic sequence around start ATG with CRISPR/Cas9\u003c/p\u003e\n\u003cp\u003eguide sequence (red letters). (B) Characterization of CRISPR/Cas9-induced gene editing events in Sox9 knockout clones. (C) Schematic representation of Sox9 protein with functionally relevant domains and their amino acid positions (Dim, dimerization domain; HMG, high mobility group DNA binding domain; K2 conserved domain K2; PQA, glutamine-rich domain; TA transactivation domain) and localization of the site targeted by CRISPR/Cas9. (D) Immunofluorescent staining of Sox9 (red) in WT O9-1 cells and Sox9-edited clones (Sox9 ko1, Sox9 ko2). DAPI served as nuclear counterstain (blue). (E) Western blot of Sox9 and beta-actin proteins in WT O9-1 cells and Sox9-edited clones in three independent samples each. (F) Quantification of Sox9 protein levels relative to beta-actin levels ± SEM as determined by Western blot. Sox9 levels in WT cells were arbitrarily set to 1. Statistical significance was determined by comparing Sox9 levels in each ko clone with WT by t-test (N = 3). (G) Quantification of Irf6 transcript levels ± SEM in WT O9-1 cells and Sox9 ko clones as determined by qRT-PCR relative to Rplp0. Irf6 transcript levels in WT cells were arbitrarily set to 1. Statistical significance was determined by comparing Irf6 transcript levels in each ko clone with WT by t-test (N = 4). Size bar: 50 μm; ***p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/52759871eaa87709a2d6e9cf.jpg"},{"id":93895533,"identity":"7f4decde-ed2b-4b73-9b62-a03436bd6927","added_by":"auto","created_at":"2025-10-20 03:10:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2453903,"visible":true,"origin":"","legend":"","description":"","filename":"WeiderWagner2025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1_covered_94813342-46eb-4855-be33-1d8717b8b65a.pdf"},{"id":93894424,"identity":"fdcd6a70-4daa-48dd-aefd-34a181048649","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":356722,"visible":true,"origin":"","legend":"","description":"","filename":"FigS1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/1105a962423f95de0a441514.jpg"},{"id":93894418,"identity":"e4b65fd6-afc7-4b1a-8091-7c36c209b92c","added_by":"auto","created_at":"2025-10-20 02:46:30","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17491,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7661291/v1/07013bb110e4c0ec5543229e.xlsx"}],"financialInterests":"","formattedTitle":"The orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-molecular-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jmme","sideBox":"Learn more about [Journal of Molecular Medicine](https://www.springer.com/journal/109)","snPcode":"109","submissionUrl":"https://submission.nature.com/new-submission/109/3","title":"Journal of Molecular Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"palate development, craniofacial development, cleft lip, cleft palate, transcriptional regulation, craniofacial developmental biology, single cell RNA-seq, single cell transcriptomics, cell-cell communication","lastPublishedDoi":"10.21203/rs.3.rs-7661291/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7661291/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Orofacial clefts represent the most prevalent congenital anomalies affecting the craniofacial region. They can be evoked by a disturbed development of either oral epithelium or cranial neural crest-derived mesenchyme, or by disruptions of their interplay. IRF6 is a well-known risk gene associated with orofacial clefts. Its expression in the oral epithelium depends on the transcription factor AP-2α, encoded by TFAP2A. We here show by immunofluorescence on mouse embryonic sections and by mining of single cell RNA-seq data that IRF6 is also expressed in cranial neural crest-derived tissue in mice and humans, together with TFAP2A and SOX9. The IRF6 enhancer MCS-9.7 can be activated by the transcription factor SOX9, mutations of which cause Pierre Robin sequence, a craniofacial anomaly that includes cleft palate. This SOX9-dependent activation is influenced by the single nucleotide variant rs76145088 that is associated with orofacial clefting. Inactivation of Sox9 in a murine neural crest cell line by CRISPR/Cas9 results in loss of Irf6 expression. We conclude that dysregulation of the SOX9–IRF6 axis in cranial neural crest cells could be relevant for the pathogenesis of orofacial clefting.","manuscriptTitle":"The orofacial cleft risk gene IRF6 is a target gene of SOX9 in cranial neural crest cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 02:46:26","doi":"10.21203/rs.3.rs-7661291/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-11-06T03:37:49+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-07T10:25:44+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-07T07:44:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-26T08:48:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Molecular Medicine","date":"2025-09-22T04:38:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-molecular-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jmme","sideBox":"Learn more about [Journal of Molecular Medicine](https://www.springer.com/journal/109)","snPcode":"109","submissionUrl":"https://submission.nature.com/new-submission/109/3","title":"Journal of Molecular Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bc526a4a-8977-4ea4-b111-1bbedf6822ee","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T12:37:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-20 02:46:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7661291","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7661291","identity":"rs-7661291","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}