Differential regulation of Wnt/beta-catenin signaling by Liver X Receptors in Schwann cells and oligodendrocytes

Abstract

Oxysterols are reactive molecules generated by the oxidation of cholesterol. Their implication in cholesterol homeostasis and in the progression of neurodegenerative disorders is well known. Here, we study the role of oxysterols and their nuclear receptors, Liver X Receptor (LXR), in myelinating glial cells of the central and peripheral nervous systems. First, we show by gas chromatography/mass spectrometry that the brain, sciatic nerve, oligodendrocytes and Schwann cells contain 24(S)-hydroxycholesterol, 25-hydroxycholesterol (25-OH) and 27-hydroxycholesterol, and they express their biosynthetic enzymes. We observed a differential effect of 25-OH toward myelin genes (MPZ and PMP22) expression: 25-OH inhibits MPZ and PMP22 in Schwann cell line but not in oligodendrocyte cell line. Importantly, the invalidation of LXR in mice enhanced MPZ and PMP22 transcripts expression in the sciatic nerve, but inhibited their expression in the brain. We have previously reported that Wnt signaling pathway is crucial for myelin gene expression. We show that the transcripts of Wnt components (Disheveled, TCF3, beta-catenin) are strongly repressed by oxysterols in Schwann cells but are activated in oligodendrocytes. Furthermore, we show by immunofluorescent labeling that beta-catenin is re-localized on the level of the Golgi apparatus of Schwann cells after incubation with 25-OH. We did not observe such an unusual localization of beta-catenin in oligodendrocytes. Our findings reveal a complex cross-talk between LXR and Wnt/beta-catenin pathway in myelinating glial cells.