Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT).

Formation of the medial edge epithelial (MEE) seam by fusing the palatal shelves is a crucial step of palate development. The opposing shelves adhere to each other at first by adherens junctions, then by desmosomes in the MEE. The MEE seam disappears by epithelial mesenchymal transformation (EMT), which creates confluence of connective tissue across the palate. Cleft palate has a mutifactorial etiology that often includes failure of adherence of apposing individual palatal shelves and/or EMT of the MEE. In this review, we first discuss TGFbeta biology, including functions of TGFbeta isoforms, receptors, down stream transcription factors, endosomes, and signalling pathways. Different isoforms of the TGFbeta family play important roles in regulating various aspects of palate development. TGFbeta1 and TGFbeta2 are involved in growth, but it is TGFbeta3 that regulates MEE transformation to mesenchyme to bring about palatal confluence. Its absence results in cleft palate. Understanding of TGFbeta family signalling is thus essential for development of therapeutic strategies. Because TGFbeta3 and its downstream target, LEF1, play the major role in epithelial transformation, it is important to identify the signalling pathways they use for palatal EMT. Here, we will discuss in detail the mechanisms of palatal seam disappearance in response to TGFbeta3 signalling, including the roles, if any, of growth and apoptosis, as well as EMT in successful MEE adherence and seam formation. We also review recent evidence that TGFbeta3 uses Smad2 and 4 during palatal EMT, rather than beta-Catenin, to activate LEF1. TGFbeta1 has been reported to use non-Smad signalling using RhoA or MAPKinases in vitro, but these are not involved in activation of palatal EMT in situ. A major aim of this review is to document the genetic mechanisms that TGFbeta uses to bring about palatal EMT and to compare these with EMT mechanisms used elsewhere.