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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024405-07
Application #
2265208
Study Section
Neurology C Study Section (NEUC)
Project Start
1987-07-01
Project End
1995-12-14
Budget Start
1994-04-01
Budget End
1995-12-14
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Eunice Kennedy Shriver Center Mtl Retardatn
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02254
Chou, Denise K H; Schachner, Melitta; Jungalwala, Firoze B (2002) HNK-1 sulfotransferase null mice express glucuronyl glycoconjugates and show normal cerebellar granule neuron migration in vivo and in vitro. J Neurochem 82:1239-51
Chou, D K; Jungalwala, F B (2001) Regulation of sulfoglucuronyl glycolipid synthesis in the developing rat sciatic nerve. Neurochem Res 26:1231-5
Henion, T R; Zhou, D; Wolfer, D P et al. (2001) Cloning of a mouse beta 1,3 N-acetylglucosaminyltransferase GlcNAc(beta 1,3)Gal(beta 1,4)Glc-ceramide synthase gene encoding the key regulator of lacto-series glycolipid biosynthesis. J Biol Chem 276:30261-9
Chou, D K; Evans, J E; Jungalwala, F B (2001) Identity of nuclear high-mobility-group protein, HMG-1, and sulfoglucuronyl carbohydrate-binding protein, SBP-1, in brain. J Neurochem 77:120-31
Zhao, Z; Nair, S M; Chou, D K et al. (2000) Expression and role of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein SBP-1 in developing rat cerebral cortex. J Neurosci Res 62:186-205
Zhao, Z; Chou, D K; Nair, S M et al. (2000) Expression of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein (SBP-1) in developing rat cerebellum. Brain Res Dev Brain Res 120:165-80
Chou, D K; Tobet, S; Jungalwala, F B (2000) Interaction of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein, SBP-1, in microexplant cultures of rat cerebellum. J Neurosci Res 59:188-201
Zhou, D; Henion, T R; Jungalwala, F B et al. (2000) The beta 1,3-galactosyltransferase beta 3GalT-V is a stage-specific embryonic antigen-3 (SSEA-3) synthase. J Biol Chem 275:22631-4
Chou, D K; Tobet, S A; Jungalwala, F B (1998) Restoration of synthesis of sulfoglucuronylglycolipids in cerebellar granule neurons promotes dedifferentiation and neurite outgrowth. J Biol Chem 273:8508-15
Nair, S M; Zhao, Z; Chou, D K et al. (1998) Expression of HNK-1 carbohydrate and its binding protein, SBP-1, in apposing cell surfaces in cerebral cortex and cerebellum. Neuroscience 85:759-71

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