Glypican‐1 ‐ Extracellular matrix interactions regulate Schwann cell differentiation

Interaction of Schwann cells, glial cells of the peripheral nervous system, with proteins in the basal lamina extracellular (ECM) matrix is required for their terminal differentiation, including the myelination of axons. Several essential Schwann cell ECM receptors that bind specific basal lamina proteins have been identified. Our laboratory has shown that membrane anchored heparan sulfate proteoglycans of Schwann cells bind heparin‐binding ECM proteins and can mediate adhesion to these substrates. A major heparin‐binding ECM protein in peripheral nerve tissue is type V collagen, which is synthesized by Schwann cells and deposited into fibrillar and basal lamina ECM. Schwann cells bind collagen V through a heparan sulfate dependent mechanism that requires a unique high affinity heparin‐binding site in the non‐collagenous N‐terminal domain (NTD) of the α 4(V) subunit. The α 4(V)‐NTD mediates heparan sulfate‐dependent Schwann cells adhesion and spreading. Several lines of evidence demonstrate that the major receptor for α 4(V)‐NTD on the Schwann cell surface is the GPI‐anchored heparan sulfate proteoglycan glypican‐1. In primary co‐cultures of Schwann cells and rat embryo neurons suppression of glypican‐1 or α 4(V) collagen expression with small interfering RNAs inhibits Schwann cell myelination. Glypican‐1 siRNA also causes a selective reduction in the incorporation of type V collagen into the Schwann cell ECM. These findings demonstrate that glypican‐1 is an ECM receptor that binds type V collagen to mediate functions that are essential for Schwann cell terminal differentiation. Supported by NIH grant NS21925.