Long term objectives of this project are to characterize early events of myelinogenesis and to gain an understanding of the process by which the expression of genes for specific myelin proteins is regulated. To this end, the genes for the major peripheral myelin glycoproteins, Po and the myelin associated glycoprotein (MAG), will be studied. Po is an integral membrane protein and is the major peripheral myelin protein; it is likely to play and important role in the structural integrity of the peripheral myelin sheath. MAG has a localization within the myelin sheath that suggests a role in mediating glial-neuronal interactions; it is also preferentially lost in acute plaques of multiple sclerosis and it is the antigenic target of paraprotein induced peripheral neuropathies further underscoring its potential importance. cDNA clones for MAG and Po will be isolated by a common strategy. Antibodies against purified MAG and Po will be used to identify, in vitro translation experiments, mRNA fractions extracted from mouse peripheral nerves, which are enriched in sequences coding for MAG and Po. These fractions will be used as probes to isolate the respective cDNAs from a mouse peripheral nerve library (to be prepared). The primary structure of the proteins will be derived from the nucleotide sequence of the MAG and Po cDNAs which will also be used to isolate the genes for Po and MAG from a genomic library. The elucidation of the structure of the genes and an evaluation of intra-exon relationships may be useful in identifying possible functional domains of the proteins. Electron microscopic heteroduplex analysis of Po and PLP may reveal common sequences reflecting a common evolutionary origin. The defect in the peripheral dysmyelinating mouse mutatn Trembler, will be studied by determining mRNA levels of MAG, Po and the MBPs. Long range goals include studying the regulation of myelin protein gene expression in a peripheral myelin tissue culture system.
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