The goals of this project are to understand the biology of oligodendrocytes (OLGs) as myelin forming and myelin maintaining cells. We have observed that following adhesion to a substratum, OLGs synthesize proteoglycans (PGs) and sulfated glycoproteins (Gps) and spatially segregate them within the plasmalemma so that the cells become polarized. Our immediate plans are to prove/disprove the following working hypothesis which states that once newly synthesized peripheral PGs and/or Gps are incorporated into the plasmalemma, they immobilize surface receptors which in turn anchor to cytoskeletal elements and thereby evoke a cytoplasmic response. We postulate that this intracellular arrangement will prove to be essential for the initiation of the biochemical events that lead to myelinogenesis. We further postulate that process extension and copious membrane synthesis, hallmarks of differentiated OLGs, are also directly linked to this sequence of events. There are a number of corollaries to the hypothesis and postulates. First, we should observe a concomitant synthesis and/or segregation of surface receptors (integral PGs and/or Gps). Second, removal of peripheral components and/or inhibition of their synthesis should result in the inhibition of: a) the biochemical events that mark OLG adhesion; b) morphological changes, e.g., process extension; and c) cytoskeletal organization. In order to test the hypothesis and its corollaries, we need to know the properties of the molecules involved. I propose to: 1) characterize OLG peripheral PGs biochemically and immunologically; 2) isolate and characterize OLG integral PGs. The work planned includes: a) establishing the number of molecular species present in each class; b) generating antibodies against selected components and utilizing them for functional studies, for studying the in situ distribution, and for screening cDNA expression libraries; and c) examining the effect of metabolic inhibitors of PGs on OLG differentiation. It is hoped that this research will throw some light on the role of PGs in the signalling events that initiate myelination and in myelination proper.
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