{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T13:42:50Z","timestamp":1793367770405,"version":"4.5.0"},"reference-count":40,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2019,3,24]],"date-time":"2019-03-24T00:00:00Z","timestamp":1553385600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE018401"],"award-info":[{"award-number":["DE018401"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE027046"],"award-info":[{"award-number":["DE027046"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:p>\n                    SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    Six2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    double-mutant mice were born with severe craniofacial deformity not seen in the Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    or Six2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    Six2\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    embryos, the E10.5 Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    Six2\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    and Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    Six2\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest\u2013specific inactivation of Six1 in Six2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    Six2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell\u2013autonomous role in frontonasal morphogenesis.\n                  <\/jats:p>","DOI":"10.1177\/0022034519835204","type":"journal-article","created":{"date-parts":[[2019,3,24]],"date-time":"2019-03-24T19:42:07Z","timestamp":1553456527000},"page":"572-579","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":51,"title":["Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development"],"prefix":"10.1177","volume":"98","author":[{"given":"Z.","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Department of Oral & Craniomaxillofacial Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Lan","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Division of Plastic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Departments of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Urology and Surgery, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Maire","sequence":"additional","affiliation":[{"name":"INSERM U1016, Institut Cochin, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral & Craniomaxillofacial Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Division of Plastic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Departments of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 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