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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:p>\n                    Proper development of the inner ear, including specification and differentiation of progenitors for the endolymphatic sac, is crucial for hearing and balance. In a mouse model of the\n                    <jats:italic toggle=\"yes\">\n                      SOX9\n                      <jats:sup>Y440X\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mutation that causes campomelic dysplasia and deafness, impaired development of the endolymphatic system at mid-gestation was associated with SOX10 downregulation. The underlying molecular causes and significance are unclear. Here, we found in\n                    <jats:italic toggle=\"yes\">\n                      Sox9\n                      <jats:sup>Y440X\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice,\n                    <jats:italic toggle=\"yes\">Sox10<\/jats:italic>\n                    expression was downregulated, prior to overt differentiation, in the dorsomedial aspect of the E10.5 otic vesicle that normally becomes the endolymphatic duct and sac. Single-cell transcriptomic profiling of E10.5 otic vesicles showed increased expression of Wnt pathway genes that was associated with the domain-specific decrease in\n                    <jats:italic toggle=\"yes\">Sox10<\/jats:italic>\n                    expression. Forced elevation of Wnt signaling by expression of stabilized \u03b2-catenin in the early otocyst and more developed inner ears, suppressed\n                    <jats:italic toggle=\"yes\">Sox10<\/jats:italic>\n                    expression. Wnt exerted an inhibitory effect on\n                    <jats:italic toggle=\"yes\">SOX10<\/jats:italic>\n                    expression in otocyst-like organoids derived from human pluripotent stem cells. In vitro transactivation assays reveal antagonistic action of SOX9 and Wnt signaling on\n                    <jats:italic toggle=\"yes\">Sox10<\/jats:italic>\n                    transactivation mediated by conserved enhancers with neighboring\/overlapping SOX9- and TCF\/LEF-binding (Wnt effectors) motifs. We propose a conserved SOX9-Wnt antagonism acting via conserved enhancers, regulates SOX10 to modulate endolymphatic cell fate. The\n                    <jats:italic toggle=\"yes\">\n                      SOX9\n                      <jats:sup>Y440X\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mutation disrupts this regulatory circuit through both dominant-negative and haploinsufficient effects culminating in impaired establishment of progenitors in the otocyst that are essential for the development of the endolymphatic system for hearing and balance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2617028123","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:03:46Z","timestamp":1791227026000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Opposing activity of SOX9 and Wnt in the developing otocyst ensures SOX10 control of endolymphatic development"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3914-2412","authenticated-orcid":false,"given":"Ka Chi","family":"Chu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2831-615X","authenticated-orcid":false,"given":"Jianning","family":"Lu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8960-3937","authenticated-orcid":false,"given":"Keith K. 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C. Chu Opposing activity of SOX9 and Wnt in the developing otocyst ensures SOX10 control of endolymphatic development. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE271849. Deposited 9 July 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2617028123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:04:03Z","timestamp":1791227043000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2617028123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":85,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2026,10,13]]}},"alternative-id":["10.1073\/pnas.2617028123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2617028123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"assertion":[{"value":"2026-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2617028123"}}