The myelin-associated glycoprotein (MAG) is localized in the periaxonal membranes of PNS and CNS myelin sheaths where is appears to be involved in glia-axon interactions. MAG is a member of the immunoglobulin gene superfamily along with other neural adhesion proteins, and alternative splicing of its mRNA generates two developmentally regulated isoforms with differing C-terminal tails. The extracellular domains of the two forms of MAG are identical with 5 immunoglobulin-like domains and 8 potential sites for N-linked glycosylation. The carbohydrate consists of a mixture of complex oligosaccharides whose structures are now under detailed investigation. The adhesion-related HNK-1/L2 carbohydrate epitope expressed on MAG is expressed at very high levels on the PO-like proteins of shark PNS and CNS myelin suggesting that it may have played an important role in the molecular evolution of myelination. The expression of MAG in cultured oligodendrocytes and Schwann cells is being studied with the ultimate objectives of identifying factors that control its synthesis and probing its function in cell-cell interactions. MAG is phosphorylated in cultured oligodendrocytes as it is in vivo, and the phosphorylation appears to be catalyzed at least in part by protein kinase C and a Ca2-activated kinase. Addition of exogenous G(M3)-ganglioside to the culture media stimulates the formation of oligodendroglial processes in a manner reminiscent of the well-established neuritogenic effects of gangliosides. Although cultured Schwann cells do not normally express MAG in the absence of neurons, some immortalized Schwann cell line generated in our laboratory express remarkably high levels of MAG, and the post-translational glycosylation, sulfation and phosphorylation in these cells is similar to that in vivo. These cell lines expressing high levels of MAG are being used to investigate the cell biology and function of this glycoprotein. An investigation of the CNS demyelination and remyelination that occurs following cuprizone treatment of mice revealed a much more severe loss of myelin basic protein and proteolipid protein than of MAG, presumably reflecting a greater loss of compact myelin than of related oligodendroglial membranes. Hypomyelination of the CNS was detected in the postmortem brains of patients with Niemann-Pick C disease similar to our previous finding of hypomyelination in its mutant mouse model with a cholesterol storage disorder.