Myelin-associated glycoprotein (MAG) is a 100,000 dalton component of the myelin membrane. The molecule is similar in structure to neural cell adhesion molecules and it has been proposed that MAG may mediate cell-cell interactions during the initial stages of myelinogenesis. In previous studies, supported by this grant, we have characterized MAG in rat brain by molecular cloning, determined the structure of the rat MAG gene and analyzed the expression of MAG mRNAs and protein in the rodent nervous system. The studies proposed here will focus on the structure of the MAG gene, the mechanisms of its regulation during myelination and remylination, and attempts to understand the function of MAG by disrupting its expression. It is the aim of the proposed studies to: 1. Analyze the mechanisms of regulation of the MAG gene. 2. Generate transgenic mice expressing regulatory regions of the MAG gene and to analyse the expression of the MAG gene in vivo. 3. Analyse the expression of the MAG gene during remyelination following a demyelinating viral infection of the central nervous system. 4. Disrupt the expression of the MAG gene, in order to asses the functional consequences of decreased or absent MAG expression on myelinogenesis. 5. Investigate the genetic defects in the mouse mutant quivering and the relationship of this mutation to the MAG gene. MAG appears to play a critical role in the early stages of myelinogenesis by mediating the initial contact between the myelinating cell and the axon and it is likely that MAG plays a similar role in remyelination following a demyelinating disease. A detailed understanding of the factors that regulate the expression of MAG will be essential for designing therapies to encourage the formation of new myelin in diseases such as multiple sclerosis.
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