AXONAL REGULATION OF SCHWANN-CELL INTEGRIN EXPRESSION SUGGESTS A ROLE FOR ALPHA-6-BETA-4 IN MYELINATION

Ensheathment and myelination of axons by Schwann cells in the peripheral nervous system requires contact with a basal lamina. 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. To initiate studies on the role of integrins during myelination, we characterized the expression of two integrin subunits, beta1 and beta4, in an in vitro myelination system and compared their expression to that of the glial adhesion molecule, the myelin-associated glycoprotein (MAG). In the absence of neurons, Schwann cells express significant levels of beta1 but virtually no beta4 or MAG. When Schwann cells are cocultured with dorsal root ganglia neurons under conditions promoting myelination, expression of beta4 and MAG increased dramatically in myelinating cells, whereas beta1 levels remained essentially unchanged. (In general agreement with these findings, during peripheral nerve development in vivo, beta4 levels also increase during the period of myelination in sharp contrast to beta1 levels which show a striking decrease.) In cocultures of neurons and Schwann cells, beta4 and MAG appear to colocalize in nascent myelin sheaths but have distinct distributions in mature sheaths, with beta4 concentrated in the outer plasma membrane of the Schwann cell and MAG localized to the inner (periaxonal) membrane. Surprisingly, beta4 is also present at high levels with MAG in Schmidt-Lanterman incisures. Immunoprecipitation studies demonstrated that primary Schwann cells express beta1 in association with the alpha1 and alpha6 subunits, while myelinating Schwann cells express alpha6beta4 and possibly alpha1beta1. Beta4 is also downregulated during Wallerian degeneration in vitro, indicating that its expression requires continuous Schwann cell contact with the axon. These results indicate that axonal contact induces the expression of beta4 during Schwann cell myelination and suggest that alpha6beta4 is an important mediator of the interactions of myelinating Schwann cells with the basal lamina.