All neurons and macroglia of adult cerebral cortex arise from proliferating neural precursor cells in the ventricular zone. Evidence is emerging that heparan sulfate proteoglycans (HSPGs) play an important role in the proliferation and differentiation of neural precursors. K-glypican is a novel member of the glypican family of GPI-anchored cell surface HSPGs which is expressed predominantly in embryonic brain and kidney. The expression of K-glypican in the brain is essentially restricted to the ventricular zone, suggesting its involvement in the growth regulation of neural precursor cells. The goal of this proposal is to elucidate the role of K-glypican and other members of the glypican family HSPGs in brain development. To achieve this goal, attack will be made from three directions. (1). The spatiotemporal expression of K-glypican and other glypican family HSPGs will be determined during embryonic development. Immunohistochemistry and in situ hybridization will be employed to define expression patterns at the sites where neurogenesis is actively occurring. The distribution of K-glypican in the adult kidney, where glypican is most highly expressed among adult organs, will also be investigated. (2). The functional properties of K-glypican and cerebroglycan on the proliferation of neural precursor cells and neurite outgrowth will be examined. In vitro assays will be used to define the biological activities of these two related HSPGs. The study will also test the hypothesis that there are functional specificities among different HSPGs. The developmental role of K-glypican in vivo will be elucidated. K-glypican knockout mice will be generated and their phenotype analyzed to define the developmental role of K-glypican. These studies not only provide new insight into the mechanism of neurogenesis but may shed light on the pathogenesis of congenital brain malformations that may derive from defective proliferation of neural precursor cells.
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