The valves and septa of the adult heart are formed in large part from embryonic """"""""cushion tissue"""""""". A majority of congenital heart defects appear to arise from the defective development of cushion tissue. The earliest cellular events of cushion tissue formation are an epithelial-to-mesenchymal cell transformation and the subsequent migration of the mesenchyme into cell-free extracellular matrix. Both of these processes require the recognition of specific extracellular matrix (ECM) molecules in order to proceed. A novel enzymatic mechanism of ECM recognition has recently been demonstrated. Cell surface galactosyltransferase (GalTase) was shown to function as a receptor during migration of another teratologically sensitive cell population, the nerual crest. Evidence is shown that the same enzyme is present during cushion tissue formation and that morphogenetic mouse mutants which display elevated levels of this enzyme have concomitant defects in cushion tissue development. This proposal examines the role of GalTase during the earliest cellular events of cushion tissue formation. Further experiments are proposed to evaluate the relationship of this particular receptor mechanism to others which may be present. To accomplish these studies, a variety of independent probes will be employed which are specific for this enzyme. Experiments will define the distribution and occurrence of the enzyme during cushion tissue formation. Specific cellular events will be isolated in culture and examined as the enzyme is perturbed by modification, competition, and catalysis. The substrate(s) recognized by this cell surface receptor will be identified by radioactive labeling. One other glycosyltransferase has been identified in the heart and will also be examined. Finally, chemical cross-linking of cushion tissue cells and cardiac TCM will be performed to examine the variety of cell:matrix interactions which may be occurring. These studies will define a specific molecular mechanism and will aid in our understanding of congenital malformations.
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