GLYCOPROTEINS AND GLYCOLIPIDS ASSOCIATED WITH MYELIN IN DEVELOPMENT AND DISEASE

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Research in this project focuses on the expression and function of glycoproteins and glycolipids in Schwann cells and oligodendrocytes during differentiation and myelination. One aspect emphasizes the myelin-associated glycoprotein (MAG) which is member of the immunoglobulin (Ig) superfamily that is localized in periaxonal glial membranes of myelinated fibers and is thought to function in transmitting signals in both directions between axons and myelin-forming cells. Current research is aimed at identifying the axonal ligand(s) for MAG and characterizing second messenger systems which are involved in MAG-mediated signaling. MAG is in the I-type lectin subgroup of the Ig superfamily and binds to glycoconjugates containing terminal alpha2-3 linked sialic acid, suggesting that its ligand could be a glycoprotein. A particularly noteworthy advance this year was the identification of a 250 kD protein in axolemma that interacts with MAG on western blots as microtubule-associated protein 1B (MAP1B). Although MAPs are thought to be cytoplasmic constituents, further studies surprisingly indicate that some MAP1B in neurons is expressed as a sialylated surface membrane glycoprotein. If MAP1B is a physiological ligand for MAG, it could function in the transmission of MAG-mediated signals that are known to affect the cytoskeletal structure of myelinated axons. Another aspect of our research in recent years concerns the expression and function of gangliosides in differentiating oligodendrocytes. GM3 increases dramatically during differentiation of cultured O-2A progenitors to become the major ganglioside in mature oligodendrocytes, and addition of exogenous GM3 to the cultures enhances differentiation in the direction of myelination. However, differentiating oligodendrocytes also express a number of minor gangliosides, including the novel sulfated gangliosides that we reported last year and O-acetylated gangliosides. O-Acetylated derivatives of GD3 and GT3 gangliosides are expressed by progenitors and are down regulated during differentiation. Furthermore, GT3 and O-acetyl-GT3 are the principal glycolipid antigens reacting with the A2B5 antibody in O-2A progenitors, and expression of both decreases in parallel with the loss of cell surface staining by this antibody during differentiation to oligodendrocytes.