The long term goal of this project is to identify and characterize the membrane components that mediate the critical axonal-glial interactions of myelination, with the view that these constituents may be implicated in the pathogenesis of demyelinating diseases. The myelin-associated glycoproteins (the MAG proteins) are integral membrane proteins of myelinating glial cells that have been proposed to maintain the apposition of the glial membrane to the axon. Their precise role during myelinogenesis however, is not known. We will use the recently isolated and myelinogenesis however, is not known. We will use the recently isolated and characterized cDNA clones for these proteins in studies intended to elucidate their physiologic role in myelination, to define their functional domains, and eventually to identify the axonal constituents with which they interact. Specifically we will: i) verify the predicted disposition of these proteins within the phospholipid bilayer as a prelude to further investigations of their structure-function relationships. We will establish the orientation of specific domains of the proteins with monospecific antibodies, as well as determining the size of protease sensitive segments of the MAG proteins which have been cotranslationally inserted into microsome membranes or are being expressed in transfected heterologous cells. ii) We will determine the role of the MAG proteins in cell adhesion by studying the interaction of permanently transfected L-cells, which express these proteins at their cell surface, in co-cultures with rat sensory neurons at both the LM and EM levels. If a specific interaction is documented, then further studies of the role of the arg-gly-asp (RGD) peptide sequence of the MAG proteins in this interaction will be undertaken. We also propose to isolate a functionally active soluble form of the MAG proteins by using non-ionic detergents or by genetically engineering a secreted form of these proteins. This will facilitate functional studies of these proteins and, in the future, may aid in the identification of their axonal receptor by cross-linking techniques. iii) We will disrupt the function of the MAG proteins in myelinated peripheral nerve cultures. We will assess the effects in these cultures of monospecific and polyclonal antibodies, as well as of a synthetic peptide corresponding to the RGD sequence of the MAG proteins on the formation and integrity of the myelin sheath and periaxonal space.
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