Epithelial Wnt/β-catenin signaling regulates palatal shelf fusion through regulation of Tgfβ3 expression

The canonical Wnt/beta-catenin signaling plays essential role in development and diseases. Previous studies have implicated the canonical Wnt/beta-catenin signaling in the regulation of normal palate development, but functional Wnt/beta-catenin signaling and its tissue-specific activities remain to be accurately elucidated. In this study, we show that functional Wnt/beta-catenin signaling operates primarily in the palate epithelium, particularly in the medial edge epithelium (MEE) of the developing mouse palatal shelves, consistent with the expression patterns of beta-catenin and several Wnt ligands and receptors. Epithelial specific inactivation of beta-catenin by the K14-Cre transgenic allele abolishes the canonical Wnt signaling activity in the palatal epithelium and leads to an abnormal persistence of the medial edge seam (MES), ultimately causing a cleft palate formation, a phenotype resembling that in Tgf beta 3 mutant mice. Consistent with this phenotype is the down-regulation of Tgf beta 3 and suppression of apoptosis in the MEE of the beta-catenin mutant palatal shelves. Application of exogenous Tgf beta 3 to the mutant palatal shelves in organ culture rescues the midline seam phenotype. On the other hand, expression of stabilized beta-catenin in the palatal epithelium also disrupts normal palatogenesis by activating ectopic Tgf beta 3 expression in the palatal epithelium and causing an aberrant fusion between the palate shelf and mandible in addition to severely deformed palatal shelves. Collectively, our results demonstrate an essential role for Wnt/beta-catenin signaling in the epithelial component at the step of palate fusion during palate development by controlling the expression of Tgf beta 3 in the MEE. (C) 2010 Elsevier Inc. All rights reserved.