The spatial arrangement of the major myelin polypeptides with respect to the phospholipid bilayer in the myelin membrane and with respect to each other will be determined and this structural information will be related to the processes of biosynthesis and assembly of the polypeptides into the developing myelin sheath. The pathway of transfer of the myelin proteolipid protein from the endoplasmic reticulum to the ensheathing process of the oligodendrocyte will be studied by cell fractionation, using pulse labelling techniques, and by immune electron microscopy. An attempt will be made to relate the disposition of the myelin polypeptides in the plasma membrane with the higher order organization of the myelin sheath. Recombinant DNA methods will be used to identify and characterize genes for the major myelin proteins. The primary structure of the myelin proteolipid protein as determined from the DNA sequence analysis, will be interpreted in light of the existence of specific structural domains identified by direct biochemical studies of the transmembrane disposition of this protein in myelin and endoplasmic reticulum membranes. The analysis of cDNA and genomic clones for the myelin basic proteins will reveal whether these are products of different members of a single gene family or are derived from the primary transcript of a single gene by differential splicing reactions. Cloned myelin basic protein cDNAs will be employed as probes to determine the molecular basis for the defect in the mouse dysmyelinating mutant """"""""Shiverer"""""""", which appears to be deficient in the synthesis of the central nervous system myelin basic proteins, and to investigate the regulatory processes by which during development different sets of myelin proteins are expressed in the central and peripheral nervous systems.
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