Leading science, pioneering therapies
CRM Publications

Regulatory mechanisms that mediate tenascin C-dependent inhibition of oligodendrocyte precursor differentiation.

TitleRegulatory mechanisms that mediate tenascin C-dependent inhibition of oligodendrocyte precursor differentiation.
Publication TypeJournal Article
Year of Publication2010
AuthorsCzopka T, Von Holst A, ffrench-Constant C, Faissner A
JournalJ Neurosci
Date Published2010 Sep 15
KeywordsAnimals, Cell Differentiation, Cells, Cultured, Central Nervous System, Down-Regulation, Female, Growth Inhibitors, Male, Mice, Mice, Knockout, Neural Inhibition, Oligodendroglia, Rats, Signal Transduction, Stem Cells, Tenascin

Here, we present mechanisms for the inhibition of oligodendendrocyte precursor cell (OPC) differentiation, a biological function of neural extracellular matrix (ECM). The differentiation of oligodendrocytes is orchestrated by a complex set of stimuli. In the present study, we investigated the signaling pathway elicited by the ECM glycoprotein tenascin C (Tnc). Tnc substrates inhibit myelin basic protein (MBP) expression of cultured rat oligodendrocytes, and, conversely, we found that the emergence of MBP expression is accelerated in forebrains of Tnc-deficient mice. Mechanistically, Tnc interfered with phosphorylation of Akt, which in turn reduced MBP expression. At the cell surface, Tnc associates with lipid rafts in oligodendrocyte membranes, together with the cell adhesion molecule contactin (Cntn1) and the Src family kinase (SFK) Fyn. Depletion of Cntn1 in OPCs by small interfering RNAs (siRNAs) abolished the Tnc-dependent inhibition of oligodendrocyte differentiation, while Tnc exposure impeded the activation of the tyrosine kinase Fyn by Cntn1. Concomitant with oligodendrocyte differentiation, Tnc antagonized the expression of the signaling adaptor and RNA-binding molecule Sam68. siRNA-mediated knockdown or overexpression of Sam68 delayed or accelerated oligodendrocyte differentiation, respectively. Inhibition of oligodendrocyte differentiation with the SFK inhibitor PP2 could be rescued by Sam68 overexpression, which may indicate a regulatory role for Sam68 downstream of Fyn. Our study therefore uncovers the first signaling pathways that underlie Tnc-induced, ECM-dependent maintenance of the immature state of OPCs.

Alternate JournalJ. Neurosci.
PubMed ID20844127
PubMed Central IDPMC3842490
Grant List / / Biotechnology and Biological Sciences Research Council / United Kingdom