title: 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.
authors.affiliation: University Paris Descartes, UMR 8194 CNRS, 45 rue des Saints-Pères, 75270, Paris Cedex 6, France.
authors.forename: Ghjuvan'Ghjacumu
authors.initials: G
authors.lastname: Shackleford
authors.forename: Joelle
authors.initials: J
authors.lastname: Makoukji
authors.forename: Julien
authors.initials: J
authors.lastname: Grenier
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.forename: Delphine
authors.initials: D
authors.lastname: Meffre
authors.forename: Charbel
authors.initials: C
authors.lastname: Massaad
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D006888:Hydroxycholesterols / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C560546:Mpz protein, mouse; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D057093:Orphan Nuclear Receptors; C489545:Pmp22 protein, mouse; D013261:Sterols; D051176:beta Catenin; C007997:25-hydroxycholesterol