CELL-CELL AND -MATRIX ADHESION IN CARDIAC MORPHOGENESIS

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One percent of newborn humans have some congenital heart defect, usually in the septation of the heart. Little is known, about the molecular bases for the cellular processes that drive the well-characterized series of morphological changes in heart development. Specific molecules involved in cell-substrate adhesion (SAMs) and cell-cell adhesion (CAMs) regulate morphogenesis in other systems and are correlated with developmentally- important primary processes such as cell migration, cell division, programmed cell death, cytodifferentiation. In the first two years of this project, we identified two SAMs, cytotactin and cytotactin-binding proteoglycan (CTB Proteoglycan), and a CAM, N-CAM, whose distributions in the heart, functions, and structures suggest that they may be involved in heart development. Our long-term goal is to determine the mechanisms through which this control is exerted by these molecules and other cell adhesion molecules. Our specific aims for this project period are to use biochemical, cell biological, molecular biological, and immunohistochemical techniques to 1) analyze the structure of CTB proteoglycan and the relationship of its structure and its function, 2) identify and characterize cell surface receptors and extracellular matrix proteins that interact with CTB proteoglycan, 3) determine the effects of cytotactin and CTB proteoglycan on the migration, proliferation, and differentiation of endocardial cushion cells which form the septation of the heart and 4) determine distribution and functions of a variant form of N-CAM found only in heart and skeletal muscle. These studies will begin to elucidate the mechanisms through which cell adhesion molecules can alter patterns of cell migration, cell division, and differentiation and thereby affect heart development.