Tenascin-R Is an Intrinsic Autocrine Factor for Oligodendrocyte Differentiation and Promotes Cell Adhesion by a SulfatideMediated Mechanism

Abstract

O4ϩ oligodendrocyte (OL) progenitors in the mammalian CNS are committed fully to terminal differentiation into myelinforming cells. In the absence of other cell types in vitro, OL differentiation reproduces the in vivo development with a correct timing, suggesting the existence of an intrinsic regulatory mechanism that presently is unknown. We have examined the effect of two isoforms of the extracellular matrix (ECM) molecule tenascin-R ( TN-R), which is expressed by OLs during the process of myelination, on the adhesion and maturation of OLs in vitro. Here we show that the substrate-bound molecules supported the adhesion of O4ϩ OLs independently of the CNS region or age from which they were derived. At the molecular level this process was mediated by protein binding to membrane surface sulfatides (Sulf ), as indicated by the interference of O4 antibody and Sulf with the attachment of OLs or other Sulf ϩ cells, erythrocytes, to TN-R substrates and by direct protein-glycolipid binding studies. In the absence of plateletderived growth factor (PDGF ), exogenous TN-R induced myelin gene expression and the upregulation of its own synthesis by cultured cells, resulting in a rapid terminal differentiation of O4 ϩ progenitors. Our findings strongly suggest that TN-R represents an intrinsic regulatory molecule that controls the timed OL differentiation by an autocrine mechanism and imply the relevance of TN-R for CNS myelination and remyelination. Key words: cell adhesion; extracellular matrix; glycosphingolipid; myelination; oligodendrocyte differentiation; sulfatide; tenascin-RIn the mammalian CNS the differentiation of oligodendrocytes (OLs) is characterized by the sequential expression of myelinspecific molecules, which finally leads to the formation of the myelin sheath. The earliest stages of macroglial development take place in the ventral regions of the neural tube (for spinal cord) and the ventricular zones of the neonatal mammalian forebrain, where the first OL progenitors characterized by simple morphology and the expression of the disialoganglioside GD3 and /or the O4 antigen(s) proliferate and migrate into the presumptive white matter

Dendritic Cells Require Multidrug Resistance Protein 1 (ABCC1) Transporter Activity for Differentiation

“…However, the finding that both sulfatide and GM1 are substrates of MRP1 might still be of distinct interest. Sulfatide has been linked to several processes like neuronal development (41), the modulation of blood coagulation (42), and tumor cell metastasis (43). As the MRP1 protein is expressed ubiquitously throughout the body and can be expressed on chemotherapy-resistant tumors, MRP1-mediated transport of sulfatide may well play a role in these processes.…”

Negative Regulation of Oligodendrocyte Differentiation by Galactosphingolipids

“…Second, sulfatide carries a negative charge and can therefore bind to positively charged proteins by electrostatic forces, a characteristic that may account for the large number of sulfatide -protein interactions (for review, see Vos et al, 1994). Of particular interest is a well documented role for sulfatide, but not for GalC, in adhesion with extracellular matrix molecules, such as tenascin-R/janusin/J-1, laminin, and thrombospondin (Roberts and Ginsburg, 1988;Pesheva et al, 1997), that are present in the CNS (McLoon et al, 1988;O'Shea et al, 1990;Bartsch et al, 1992) and are secreted by the OLs and/or astrocytes in culture (Oh and Yong, 1996;Pesheva et al, 1997).…”

“…In fact, integrin-mediated inhibition of OL differentiation (similar to that induced by anti-galactolipids) occurs in OL cultures treated with RGD peptide, a sequence in the EC M molecules recognized by the integrins (Cardwell and Rome, 1988;Malek-Hedayat and Rome, 1994). Similarly tenascin-R, which is secreted by OLs in culture (Pesheva et al, 1997), binds to both sulfatide and F3/F11/ contactin (Nörenberg et al, 1995) on the OL surface (Koch et al, 1997;Pesheva et al, 1997). F3 intern binds to Fyn, a nonreceptor tyrosine kinase that is implicated as an important signaling molecule in OL development and myelin formation (Osterhout et al, 1999;Umemori et al, 1999).…”

Role of sulfatide in normal and pathological cells and tissues

“…Because the hydroxy FAs originate from myelinating oligodendrocytes in gray matter, sulfatide with the hydroxy FAs is suggested to infl uence myelin stability ( 26 ). On the other hand, the myelin formation of cultured Schwann cells appears to be initiated by sulfatide through its binding to extracellular matrixes, like tenascin-R or laminin, which binds to integrins (signaling molecules) and can stimulate c-Src/Fyn kinase (27)(28)(29). Histological analysis showed that axons of the optic nerve in CST-defi cient mice were well-myelinated.…”