TENASCIN-R IS AN INTRINSIC AUTOCRINE FACTOR FOR OLIGODENDROCYTE DIFFERENTIATION AND PROMOTES CELL-ADHESION BY A SULFATIDE-MEDIATED MECHANISM

O4(+) oligodendrocyte (OL) progenitors in the mammalian CNS are commit ted fully to terminal differentiation into myelin-forming cells. In th e absence of other cell types in vitro, OL differentiation reproduces the in vivo development with a correct timing, suggesting the existenc e of an intrinsic regulatory mechanism that presently is unknown. We h ave examined the effect of two isoforms of the extracellular matrix (E CM) molecule tenascin-R (TN-R), which is expressed by OLs during the p rocess of myelination, on the adhesion and maturation of OLs in vitro. Here we show that the substrate-bound molecules supported the adhesio n of O4(+) OLs independently of the CNS region or age from which they were derived. At the molecular level this process was mediated by prot ein binding to membrane surface sulfatides (Sulf), as indicated by the interference of O4 antibody and Sulf with the attachment of OLs or ot her Sulf(+) cells, erythrocytes, to TN-R substrates and by direct prot ein-glycolipid binding studies. In the absence of platelet-derived gro wth factor (PDGF), exogenous TN-R induced myelin gene expression and t he upregulation of its own synthesis by cultured cells, resulting in a rapid terminal differentiation of O4(+) progenitors. Our findings str ongly suggest that TN-R represents an intrinsic regulatory molecule th at controls the timed OL differentiation by an autocrine mechanism and imply the relevance of TN-R for CNS myelination and remyelination.