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. Substantial evidence supports the premise that various signal transduction systems interact to regulate cell proliferation and cell differentiation during embryogenesis in general and development of the palate in particular. Such interactions studies outlined in this subproject 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. Past studies conducted in our laboratory have provided fascinating insights regarding the role of various cellular signal transduction pathways, particularly TGFbeta and cAMP/cAMP-dependent protein kinase (PKA) mediated signaling processes, in regulation of both growth and differentiation in embryonic orificial tissue. This competing continuation application extends our observations and proposes studies to: examine whether TGF-beta-mediated signal transduction in embryonic palatal tissue involves protein kinase activity (aim #1); determine whether the effects of TGFbeta on gene expression involve phosphorylation of specific transcription factors (aim #2); identify and characterize specific protein phosphatases that regulate kinase activity specific transcription factors is regulated by phosphatase-mediated dephosphorylation (aim #4); and define specific cellular sites of 'crosstalk' between the protein kinase A and retinoic acid signal transduction pathways in embryonic palatal tissue (aim #5).