title: Convergent functional genomics of oligodendrocyte differentiation identifies multiple autoinhibitory signaling circuits.
abstract: Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a critical role in oligodendrocyte differentiation, we performed time-dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into process-forming and myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the completely differentiated state, where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using small interfering RNA and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNP, a well-known myelin constituent, and three phosphatases, each known to negatively control mitogen-activated protein kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition.
authors.affiliation: Merck Serono SA, 9, Chemin des Mines, 1211 Geneva, Switzerland.
authors.forename: Rosanna Pescini
authors.initials: RP
authors.lastname: Gobert
authors.forename: Lara
authors.initials: L
authors.lastname: Joubert
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Curchod
authors.forename: Catherine
authors.initials: C
authors.lastname: Salvat
authors.forename: Isabelle
authors.initials: I
authors.lastname: Foucault
authors.forename: Catherine
authors.initials: C
authors.lastname: Jorand-Lebrun
authors.forename: Marc
authors.initials: M
authors.lastname: Lamarine
authors.forename: Hélène
authors.initials: H
authors.lastname: Peixoto
authors.forename: Chloé
authors.initials: C
authors.lastname: Vignaud
authors.forename: Christèle
authors.initials: C
authors.lastname: Frémaux
authors.forename: Thérèse
authors.initials: T
authors.lastname: Jomotte
authors.forename: Bernard
authors.initials: B
authors.lastname: Françon
authors.forename: Chantal
authors.initials: C
authors.lastname: Alliod
authors.forename: Lilia
authors.initials: L
authors.lastname: Bernasconi
authors.forename: Hadi
authors.initials: H
authors.lastname: Abderrahim
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrin
authors.forename: Agnes
authors.initials: A
authors.lastname: Bombrun
authors.forename: Francisca
authors.initials: F
authors.lastname: Zanoguera
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Rob
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D051379:Mice; D004676:Myelin Basic Protein / Q000096:biosynthesis; D055495:Neurogenesis / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004676:Myelin Basic Protein; D005576:Colforsin; D014212:Tretinoin; D003907:Dexamethasone; D054637:Dual-Specificity Phosphatases