1. p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate.
- Author
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Richardson R, Mitchell K, Hammond NL, Mollo MR, Kouwenhoven EN, Wyatt ND, Donaldson IJ, Zeef L, Burgis T, Blance R, van Heeringen SJ, Stunnenberg HG, Zhou H, Missero C, Romano RA, Sinha S, Dixon MJ, and Dixon J
- Subjects
- Animals, Cell Movement genetics, Cell Proliferation genetics, Cleft Palate physiopathology, Disease Models, Animal, Epithelial Cells metabolism, Gene Expression Regulation, Developmental, Humans, Mice, Mutation, Phosphoproteins biosynthesis, Signal Transduction genetics, Trans-Activators biosynthesis, Cleft Palate genetics, Gene Regulatory Networks genetics, Phosphoproteins genetics, Trans-Activators genetics, Transforming Growth Factor beta3 genetics
- Abstract
Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of cleft palate; however, the gene regulatory networks in which p63 functions remain only partially characterized. Our findings demonstrate that p63 functions as an essential regulatory molecule in the spatio-temporal control of palatal epithelial cell fate to ensure appropriate fusion of the palatal shelves. Initially, p63 induces periderm formation and controls its subsequent maintenance to prevent premature adhesion between adhesion-competent, intra-oral epithelia. Subsequently, TGFβ3-induced down-regulation of p63 in the medial edge epithelia of the palatal shelves is a pre-requisite for palatal fusion by facilitating periderm migration from, and reducing the proliferative potential of, the midline epithelial seam thereby preventing cleft palate.
- Published
- 2017
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