Dystroglycan is a molecule that is directly relevant to the pathology underlying muscular dystrophy and perhaps other human diseases. However, the basic function of dystroglycan remains unclear. The dystroglycan knockout mouse displays an early embryonic lethal phenotype with defects in Reichert's membrane- an embryonic basement membrane. The detailed phenotype suggests the hypothesis that dystroglycan is required for the assembly of extracellular matrix proteins into a basement membrane structure. The experiments outlined in this proposal are designed to test this hypothesis as a step toward the long term goal of understanding the biological role of dystroglycan. The four specific aims of this proposal are: 1) Determination of the molecular and cellular basis for the defect in Reichert's membrane in dystroglycan knockout embryos; 2) Analysis of the role of dystroglycan in Reichert's membrane assembly in an organ culture system; and, 3) Analysis of basement membrane assembly in embryoid bodies derived from dystroglycan-null ES cells. The experiments supporting these aims involve in situ analysis of dystroglycan knockout embryos, and the use of cell and organ culture models to test dystroglycan's role in basement membrane assembly. Since basement membranes are fundamental features of normal tissue structure and function, understanding dystroglycan's role in their development should have importance for understanding human disorders involving basement membranes, such as the muscular dystrophies.
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