P63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate.

Rose Richardson,Huiqing Zhou,Michael J Dixon,Karen Mitchell,Caterina Missero,Maria Rosaria Mollo,Rose Anne Romano,Nigel L Hammond,Hendrik G Stunnenberg,Niki D Wyatt,Satrajit Sinha,Rognvald Blance,Tim Burgis,Jill Dixon,Leo Zeef,Evelyn N Kouwenhoven,Ian J Donaldson,Simon J Van Heeringen

doi:10.1371/journal.pgen.1006828

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.

Highlights

Cleft palate is a common congenital anomaly with a prevalence estimated at 1:2500 live births, that results from failure of growth, elevation, adhesion and/or fusion of the palatal shelves during embryogenesis [1,2]
Genes to regulate palate development is not well understood.In this study, we demonstrate that p63 controls the spatio-temporal regulation of palatal epithelial cell fate to ensure appropriate palatal adhesion: p63 induces the formation of a flattened layer of epithelial cells and controls its subsequent maintenance
As p63 expression is maintained in the medial edge epithelia (MEE) of Tgfb3-/- mice which exhibit cleft palate and persistent periderm cells over the MEE [12,19,23,24], we manipulated the level of p63 in the MEE of Tgfb3-/- mice genetically

Summary

Introduction

Cleft palate is a common congenital anomaly with a prevalence estimated at 1:2500 live births, that results from failure of growth, elevation, adhesion and/or fusion of the palatal shelves during embryogenesis [1,2]. The frequent occurrence and resulting major healthcare burden highlight the need to dissect the mechanisms that underlie development of the secondary palate and how they are disturbed in cleft palate [2]. Palatal shelves initiate from the maxillary processes on embryonic day (E) and grow vertically, lateral to the tongue, during E12 and E13. At these stages, each palatal shelf consists of a core of neural crest cell-derived mesenchyme surrounded by a simple, undifferentiated epithelium consisting of a basal layer of cuboidal ectodermal cells and a surface layer of flattened periderm cells [4,5]. The MEE of the apposed palatal shelves adhere to form a midline epithelial seam (MES) which subsequently degenerates to allow mesenchymal continuity across the palate by E15.5 [3]

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Conclusion