MEDIATORS OF TGF BETA SIGNALING IN PALATE DEVELOPMENT

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To elucidate the signal transduction pathway (molecular and nuclear mechanisms of gene regulation) responsible for the effects of TGFbeta on proliferation and differentiation during palatal development. The embryonic development of the orofacial area requires precise patterns of proliferation and differentiation. Central to these processes is the cell cycle which functions to integrate the vast array of incoming information and to coordinate the complex cytoplasmic and nuclear processes leading to either division or differentiation. One of the pivotal regulators of the cell cycle is the E2F family of transcription factors which functions to control the expression of those genes necessary for passage through the restriction point and the subsequent replication of genetic material during the S phase. The activity of E2F is controlled by a number of factors including formation of complexes with the products of the Retinoblastoma gene family (pRb, p107, p130). Although much is known concerning the role of E2Fs and pRbs in disturbances of growth and differentiation such as malignancy, their role in palatal development and the effects of various growth factors on their function has yet to be delineated. One growth factor having profound effects on the developing palate is TGFbeta which inhibits cellular proliferation and stimulates synthesis of extracellular matrix in palatal mesenchymal cells while also inducing differentiation of the medial edge epithelium. Since TGFbeta is known to affect multiple components of the cell cycle (including the pRbs and E2Fs) in other tissues and cell types, our hypothesis is that TGFbeta influences craniofacial development via an arrest of the cell cycle which is mediated by changes in the expression and the activity of the E2F family of transcription factors and by alterations in the interactions between the E2Fs and the Rb family of phosphoproteins.