{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:10:22Z","timestamp":1784247022785,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Craniofacial development requires intricate cooperation between multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the role of Six1 in mandible development using a <jats:italic>Six1<\/jats:italic> knockout mouse model (<jats:italic>Six1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) and a cranial neural crest-specific, <jats:italic>Six1<\/jats:italic> conditional knockout mouse model (<jats:italic>Six1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>; Wnt1-Cre<\/jats:italic>). The <jats:italic>Six1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Notably, the <jats:italic>Six1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>; Wnt1-Cre<\/jats:italic> mice recapitulate the microsomia phenotype of <jats:italic>Six1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, thus demonstrating that the expression of <jats:italic>Six1<\/jats:italic> in ectomesenchyme is critical for mandible development. We further showed that the knockout of <jats:italic>Six1<\/jats:italic> led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of <jats:italic>Six1<\/jats:italic> in C3H10 T1\/2 cells reduced their osteogenic capacity <jats:italic>in vitro<\/jats:italic>. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and Six1 knockdown in C3H10 T1\/2 led to the dysregulation of genes involved in embryonic skeletal development. In particular, we showed that Six1 binds to the promoter of <jats:italic>Bmp4<\/jats:italic>, <jats:italic>Fat4<\/jats:italic>, <jats:italic>Fgf18,<\/jats:italic> and <jats:italic>Fgfr2<\/jats:italic>, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in regulating mandibular skeleton formation during mouse embryogenesis.<\/jats:p>","DOI":"10.3389\/fgene.2023.1082911","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T06:08:02Z","timestamp":1675836482000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Ectomesenchymal Six1 controls mandibular skeleton formation"],"prefix":"10.3389","volume":"14","author":[{"given":"Songyuan","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/sj.cr.7290185","article-title":"Msx homeobox gene family and craniofacial development","volume":"13","author":"Alappat","year":"2003","journal-title":"Cell Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"108656","DOI":"10.1016\/j.celrep.2020.108656","article-title":"FOS licenses early events in stem cell activation driving skeletal muscle regeneration","volume":"34","author":"Almada","year":"2021","journal-title":"Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1241006","DOI":"10.1126\/science.1241006","article-title":"Fine tuning of craniofacial morphology by distant-acting enhancers","volume":"342","author":"Attanasio","year":"2013","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","first-page":"dev176776","DOI":"10.1242\/dev.176776","article-title":"Dchs1-Fat4 regulation of osteogenic differentiation in mouse","volume":"146","author":"Crespo-Enriquez","year":"2019","journal-title":"Development"},{"key":"B5","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.ydbio.2011.02.031","article-title":"Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung","volume":"353","author":"El-Hashash","year":"2011","journal-title":"Dev. 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