Heparin sulfate (HS) proteoglycans are found ubiquitously on cell surfaces where, through the binding of """"""""heparin-binding"""""""" proteins that include growth factors, extracellular matrix proteins, cell-cell adhesion molecules, and molecules involved in various degradative pathways, they play key roles in a number of developmental and pathological processes. Recent identification of both murine and Drosophila mutations in heparan sulfate biosynthetic enzymes, each with profound defects in morphogenesis, serves to underscore the importance of cell surface proteins that bear this post-translational modification. Predominantly, cell surface heparan sulfate is found attached to two distinct families of proteoglycans, glypicans and syndecans. We have studied the glypican gene family and found that individual glypicans have remarkably specific developmental patterns of expression suggesting unique functions, and based on the evolutionary relationship of this gene family, we have hypothesized that structurally related subfamilies of glypicans may have functions which are somehow related. Recently identified loss of function mutations in human glypican-3 (Simpson-Golabi-Behmel syndrome) and the Drosophila glypican dally, suggest that at least some glypicans do have critical activities in vivo and strongly suggests that these functions relate to cellular growth control and morphogenesis. The molecular mechanisms of normal glypican-e function in vivo are completely unknown, as is the precise relationship between the loss of function of this gene and the pathophysiology of Simpson-Golabi-Behmel syndrome in humans. Our immediate objective is to improve our understanding of these processes by attempting to understand the structural features of glypican-e critical to its function in vivo, focusing specifically on the phenotype of renal cystic medullary dysplasia found in both humans and mice bearing loss of function mutations of the glypican-3e gene. Molecular genetic approaches will be used in transgenic mice to test the ability of wild-type murine glypican-3, mutated or modified glypican-3, as well as other heparan sulfate proteoglycans to rescue this renal phenotype. These short-term objectives will further our long-term objectives which are to identify the ligands and biochemical pathways through which glypicans act in both normal and abnormal human morphogenesis.
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