Résumé :
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Glucocorticoids play a major role in the nervous system and promote myelination. Their action is mediated by the glucocorticoid receptor (GR) that recruits coactivators(CBP or p300). We investigated the role of CBP and p300 in Schwann cells. We showed that neither CBP nor p300 enhanced GR transcriptional activation and unexpectedly, p300 acted as a corepressor. Functional and pull-down assays showed that beta catenin is the coactivator replacing CBP in the GR transcriptional complex, indicating that glucocorticoids may act by means of unusual partners in Schwann cells. Beta catenin is involved in Wnt signaling pathway which plays a role in development and diseases. We have then evaluated the physiological significance of our findings, by studying the regulation of myelin genes expression by glucocorticoids and Wnt/beta catenin. We showed that P0 and PMP22 genes (two major peripheral myelin genes) are stimulated by Wnt pathway, moreover, the combination of of glucocorticoids and Wnt signaling have a synergistic effect (i.e. 13-fold stimulation of P0 gene expression). We have then studied the mechanism of regulation of myelin genes by Wnt signaling by using either siRNA targeting beta catenin and LEF/TCF, or dominant-negative forms of the receptor frizzled and Disheveled. We found that Wnt/beta catenin pathway is essential for both basal and stimulated activities of myelin genes. Finally, we have studied the cross-talk between the GR and Wnt/beta catenin pathways and found that glucocorticoid enhances the expression of beta catenin, which is able to bind to GR and TCF. Our findings highlight the importance of Wnt/beta catenin and glucocorticoid in the expression of myelin genes, and opens a new strategy in the treatment of demyelinating disease such as Charcot-Marie-Tooth by modulating the action of Wnt/beta catenin and glucocorticoid pathways.
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