Tyrosine kinases and tyrosine phosphatases have been shown to play various important roles in cellular metabolism and in embryonic development. Several lines of evidence suggest that intracellular signalling via tyrosine phosphorylation may play an important role in craniofacial development. The peptide growth factors TGFalpha and PDGF, both of which have been shown to be involved in palate development, exert their effects through receptors that possess tyrosine kinase activity. The environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin, a powerful inducer of palatal clefts in sensitive murine strains, also causes abnormal expression patterns of the TGFalpha/EGF receptor in the palate and has been shown to affect protein tyrosine: phosphorylation in cultured cells. Finally, murine strains that carry certain mutations involving tyrosine kinase signalling pathways, such as the mutant Patch, also display severe craniofacial: abnormalities, including cleft palate. Taken together, these observations suggest that tyrosine phosphorylation plays a critical regulatory role in normal craniofacial development. Little is known at present about the functioning of tyrosine kinase-mediated signalling systems in the palate. We therefore propose these pilot studies to identify elements of such pathways in the developing palate. These studies will provide data that can be used as the basis for more detailed analyses in the future.
The specific aims of this study are as follows: 1) Identify the major endogenous phosphotyrosine-containing proteins in palate tissue during the period of palatal development 2) Determine if endogenous tyrosine kinase activity is developmentally regulated. 3) Determine if TGFalpha is involved in regulation of protein tyrosine phosphorylation in the developing palate. 4) Determine the feasibility of the murine mutant Patch as a model for studying the role of tyrosine kinase signaling in palate development.
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