p63 and IRF6: brothers in arms against cleft palate

Abstract

Cleft lip and cleft palate, which can also occur together as cleft lip and palate, are frequent and debilitating congenital malformations, with complex geneses that have both genetic and environmental factors implicated. Mutations in the genes encoding the p53 homolog p63 and interferon regulatory factor 6 (IRF6) are major causes of cleft lip and cleft palate, but the molecular and cellular mechanisms underlying this have not been clear. However, in this issue of the JCI, Thomason et al. and Moretti et al. independently show that p63 and IRF6 operate within a regulatory loop to coordinate epithelial proliferation and differentiation during normal palate development. Disruption of this loop as a result of mutations in p63 or IRF6 causes congenital clefting.

Figure 1. Development of the mouse secondary palate and human CL/CP.

(A–G) Histological sections of mouse embryo heads, showing the development sequences of the secondary palate. (A) At E14, the PSs are vertically oriented in the oral cavity. (B) At E14.5, the PSs have elevated to a horizontal position above the dorsum of the tongue (T). (C and D) At E15, adhesion of the PSs, through their MEE, creates the MES. (D) A high-magnification image of the PS shown in C. (E) Immunohistochemistry showing expression of zonula occludens 1, a tight junction component (dark color), in the regressing MES and the rest of the palate epithelium. (F) Immunostaining for cleaved lamin A, showing apoptotic cells (dark spots indicated by arrows) in the MES and in the epithelial seam at the nasopalatine junction (NPJ), the site of adhesion between the PS and the nasal septum. (G) Successful closure of the palate (P) at E15.5 leads to the separation of the oral and the nasal cavities (NC). (H) Infant with unilateral total clefts of the lip, alveolar ridge, primary palate, and secondary palate. Asterisks indicate tooth primordia. Scale bars: 500 μm (A–C and G); 100 μm (D and F); and 50 μm (E).