β4 integrin expression in myelinating Schwann cells is polarized, developmentally regulated and axonally dependent

In developing and regenerating peripheral nerve, Schwann cells interact with axons and extracellular matrix in order to ensheath and myelinate axons. Both of these interactions are likely to be mediated by adhesion molecules, including integrins, which mediate cell-cell and cell-extracellular matrix interactions. Recently, the β4 integrin subunit was reported to be expressed by Schwann cells in peripheral nerve. We have examined the expression of β4, β1 and their common heterodimeric partner, the α6 integrin subunit, in developing and regenerating rat peripheral nerve. β4 and α6 are enriched in peripheral nerve and they co-localize at the abaxonal surface of myelinating Schwann cells, opposite the Schwann cell basal lamina, which contains possible ligands of α6β4. In contrast, β4 and α6 are expressed in a different pattern in non-myelinating Schwann cells. The level of 4, but not α6 or β1 mRNAs, increases progressively in developing nerves, reaching a peak in adult nerves well after the peak of the myelinspecific mRNAs. After axotomy, the expression of β4 mRNA and protein, but not α6 or β1 mRNAs, fall rapidly but subsequently are reinduced by regenerating axons. Similarly, in cultured Schwann cells, the expression of β4 mRNA, but not α6 mRNA, is significantly modulated by forskolin, a drug that elevates cAMP and mimics some of the effects of axonal contact. β4 integrin expression in Schwann cells, therefore, is regulated by Schwann cellaxon interactions, which are known to be critical in determining the Schwann cell phenotype. Furthermore, the polarized expression of α6β4 to the abaxonal surface of myelinating Schwann cells suggests that α6β4 may mediate in part the morphological changes required of Schwann cells in the process of myelination in the peripheral nervous system.