title: Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence.
abstract: Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role ofSox11in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression inSox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans.
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Huarong
authors.initials: H
authors.lastname: Huang
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Bao
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Cao
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China.
authors.forename: Mengsheng
authors.initials: M
authors.lastname: Qiu
authors.affiliation: From the Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory for Mammalian Organogenesis and Regeneration, College of Biological and Environmental Science, Hangzhou Normal University, Zhejiang 310036, China zunyi_zhang@idrbio.org.
authors.forename: Zunyi
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D051525:Fibroblast Growth Factor 9 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008334:Mandible / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010159:Palate / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D010855:Pierre Robin Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055751:SOXC Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014059:Tongue / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse; D019938:Cyclin D1; D001973:Bromodeoxyuridine
keywords: FGF; Pierre Robin sequence; Sox11; cell proliferation; cleft palate; craniofacial development; gene regulation; micrognathia; mouse
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