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

ABSTRACT: 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.

SUBMITTER: Czopka T

PROVIDER: S-EPMC3842490 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Czopka Tim T von Holst Alexander A ffrench-Constant Charles C Faissner Andreas A

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100901 37

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 emergen ...[more]

PMID: 20844127

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Project description:We used transcription-profiling to identify mitogen-activated protein kinase (Mapk) signaling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signaling by elevation of intracellular levels of cAMP using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolyzing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. Study was conducted to identify the genes that are differentialy regulated during early time point of OPC differentiation. This study includes reanalyzed data from the following 6 Samples available in GSE24821: [i] 5 days post lesion (dpl) laser captured caudal cerebellar peduncle (CCP) replicates 1-3 (GSM610956-GSM610958), and [ii] 14 dpl laser captured CCP replicates 1-3 (GSM610959-GSM610961). For the reanalyzed data, raw data files were background-corrected, normalized and summarized using the RMA algorithm as implemented in the R statistical programming environment (http://www.r-project.org). Differential expression between sample groups was assessed using the moderated t-test as implemented in the limma package for the Bioconductor suite of R bioinformatics software (http://bioconductor.org). In order to correct for hypothesis testing on such a scale, P-values relating to differential expression were corrected for multiple testing using FDR correction. Differential expression across sample groups was deemed significant at an FDR of 5% (q < 0.05). The processed data for the reanalyzed dataset is linked below as supplementary file 'GSE50042_reanalyzed_Samples.txt'. The processed data for Samples GSM1213100-GSM1213114 is linked below as supplementary file 'GSE50042_processed_data.txt'.

Dataset Information

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

Publications

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

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