THE ROLE OF TGF-BETA3 IN PALATOGENESIS

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The long-term goal of this proposal is to define specific molecular mechanisms of TGF-beta3-induced palatal fusion. During development TGF-beta3 expression is both spatially and temporally restricted. Exceptionally high expression levels have been found specifically in prefusion palatal epithelium. Concordant with this surge of TGF-beta3 expression, homozygous TGF-beta3-deficient mice suffer from bilateral clefting of the secondary palate. It has been suggested that during epithelial fusion, TGF-beta3 triggers epithelio-mesenchymal transdifferentiation and associated degradation of the basement membrane, processes necessary for successful palatal fusion. The combined data, including expression pattern and level of TGF-beta3 in prefusion palatal shelves, complete penetrance of cleft palate in TGF- beta3 null mutant mice and failure of TGF-beta3-deficient medial edge epithelial cells to transdifferentiate from epithelial cells to mesenchymal cells lead to the formulation or the following hypotheses: TGF beta3 is a master switch, capable of initiating a cascade of molecular events leading to successful midline epithelial fusion during palatogenesis. To test this hypothesis we will utilize TGF-beta3 null mutant mice to investigate TGF-beta3 signaling and downstream biological responses. The proposed studies have been organized to three different Aims: expression and function of TGF-beta type I receptors and their down- stream signaling molecules, Smads in Aim 1, role of epithelial mastergenes and key molecular switches in epithelio-mesenchymal transdifferentiation during epithelial fusion in Aim2, and function of metalloprotemases and their inhibitors during associated degradation of the basement membrane in Aim 3. These studies will eventually improve our understanding of the pathogenetic mechanisms that lead to formation of cleft palate, one of the most common congenital birth defects in human.