NEUROBIOLOGY OF SULFATED GLUCURONYL GLYCOCONJUGATES

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The major long term goal of this project is to understand the role and function of sulfoglucuronyl glycolipids (SGGLs) and other neolacto series of glycolipids which are stage specific and developmentally regulated antigens in the cortex in the central nervous system, during the important period of cell differentiation and cell migration. The carbohydrate moiety of SGGLs is highly immunogenic and monoclonal antibodies such as HNK-1, which bind to the carbohydrate also react with either the same or similar epitope on several important glycoproteins involved in cellular interaction, such as neural cell adhesion molecules, N_CAMs, L1, J1, tenascin, cytotactin, integrin, NILE, myelin associated glycoprotein and PO protein. The proper development of the nervous system depends upon these molecules. Although SGGLs are expressed in the cortex during embryonic and neonatal development only, they are associated with Purkinje cells and in peripheral nervous system, even in the adult. The present specific aims are to understand the biochemical regulation of their differential expression in these areas of the nervous system by studying the enzymes involved in the metabolism of these lipids. Enzymes include several glycosyltransferases and glycosidases. Besides SGGLs other neolactoseries of glycolipids having the same backbone, such as fuconeolactotetraoside and ganglioside LD1 are also developmentally regulated antigens to their proper location in the cortex during development. Cells expressing specific carbohydrates will be studied in vitro to evaluate the role of these antigens in maturation and differentiation. SGGLs and sulfatide act as ligand cell-adhesion between cell-cell, cell-substratum and bind extracellular matrix protein laminin. Studies are planned to characterize a 30 kD SGGL/sulfatide binding protein from developing cortex and cerebellum. The protein and antibodies to this protein will be used as probes to investigate the role of SGGLs and of the HNK-1 reactive proteins in cellular interactions. New fixation method has been developed to differentiate immunocytochemical localization of HNK-1 reactive lipids versus proteins in neural tissues. This method will be used to precisely localize the expression of lipid versus protein antigens, at light and electron microscopic level during development of the cortex and cerebellum, and in certain mutants. Cellular and subcellular localization of these molecules may provide new clues as to their functional role.