Striking changes in the morphology and differentiation of Schwann cells and oligodendrocytes occur during myelination. These events are likely to be regulated by adhesion molecules that are expressed at the surface of these cells and involve dramatic change in the organization of the cytoskeleton. In the peripheral nervous system contact with the basal lamina regulates Schwann cell ensheathment and myelination of axons. The molecular mechanism(s) by which the basal lamina promotes myelination is not known but is likely to reflect the activity of integrins expressed by Schwann cells. We have recently found that there is a dramatic change in the pattern of integrin expression during Schwann cell myelination, from alpha6beta1 to alpha6beta4, which is regulated by axonal contact. These findings, in turn, suggest that there is a transition in the transmembrane linkage of the Schwann cell with extracellular matrix from actin filaments in ensheathing cells to intermediate filaments in myelinating cell and have important implication for the dramatic morphologic changes of myelination. By contrast, very little is known about the expression or role of integrins in oligodendrocytes and their precursors and whether their expression is similarly regulating during differentiation. To continue our studies on the role of integrins in myelination we propose to; i) inhibit the function and modulate the expression of the major Schwann cell integrins using antibodies and recombinant DNA strategies respectively and then determine the consequence of these perturbations on myelin formation in vitro ii) characterize the reorganization of the Schwann cell cytoskeleton, with a particular emphasis on intermediate filaments and a unique intermediate filament associated protein, skelemin, during myelination, and iii) characterize the expression of beta1 integrins at different stages of the oligodendroglia lineage. Oligodendrocyte progenitors will be grown in different tissue culture conditions to regulate their differentiation; mature oligodendrocytes will be isolation by a novel method using the MBP promoter to drive the expression of a selectable marker. The effect of anti-beta1 antibodies on oligodendrocyte myelination in cocultures will also be assessed. These studies would provide important new insights into tahe molecular mechanisms by which integrins regulate the migration and differentiation of myelinating glial cell.
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