Craniofacial malformations occur with a frequency of 1 in 600 live births annually in the United States. Since the causes of abnormal formation of the palate are largely unknown, basic science research into the molecular regulatory mechanisms responsible for normal development of the palate is essential in order to provide the framework for investigations into the etiology of palatal clefts. Our previous studies have provided documentation of unique temporal and spatial patterns of expression of the transforming growth factors beta (TGFbetas) and their receptors as well as the ability of the TGFbetas to regulate proliferation and metabolism of several extracellular matrix components in developing palatal tissue. Substantial evidence supports the premise that various signal transduction systems interact to regulate cell proliferation and cell differentiation during embryogenesis. Such interactions represent the underpinnings of complex and delicately balanced developmental systems. The studies outlined in this application propose to demonstrate that several signaling molecules are components of a coordinated regulatory system, wherein several different signaling pathways integrate with one another. Such a regulatory system thereby provides multiple levels of regulation and exquisite control of gene expression in embryonic palatal tissue. The current application will extend the findings of the previous funding period and proposes specific studies to examine; the amounts of mature biologically active TGFbeta and various latent complexes of TGFbeta protein synthesized during development of the palate (aim #1, factors that regulate synthesis of TGFbeta isoforms (aim #2) and their receptors (aim #4) in embryonic palatal tissue, whether intracellular TGFbeta-mediated signal transduction is mediated bia protein phosphorylation (aim #5), and how this signal transduction pathway interacts with the retinoic acid signaling pathway, also relevant to embryonic orofacial development (aim #3). Molecular analyses of gene function in the embryo utilizing the developing craniofacial region, thus promise definition and clarification of developmental pathways critical for normal embryogenesis as well as identification of foci for perturbation and attendant craniofacial dysmorphogenesis.
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