Convergent functional genomics of oligodendrocyte differentiation identifies multiple autoinhibitory signaling circuits.
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.
Gobert
Rosanna Pescini
RP
Merck Serono SA, 9, Chemin des Mines, 1211 Geneva, Switzerland.
Joubert
Lara
L
Curchod
Marie-Laure
ML
Salvat
Catherine
C
Foucault
Isabelle
I
Jorand-Lebrun
Catherine
C
Lamarine
Marc
M
Peixoto
Hélène
H
Vignaud
Chloé
C
Frémaux
Christèle
C
Jomotte
Thérèse
T
Françon
Bernard
B
Alliod
Chantal
C
Bernasconi
Lilia
L
Abderrahim
Hadi
H
Perrin
Dominique
D
Bombrun
Agnes
A
Zanoguera
Francisca
F
Rommel
Christian
C
Hooft van Huijsduijnen
Rob
R
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
D004676:Myelin Basic Protein; D005576:Colforsin; D014212:Tretinoin; D003907:Dexamethasone; D054637:Dual-Specificity Phosphatases