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Molecular and Cellular Biology, March 2009, p. 1538-1553, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01375-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Convergent Functional Genomics of Oligodendrocyte Differentiation Identifies Multiple Autoinhibitory Signaling Circuits{triangledown} ,{dagger}

Rosanna Pescini Gobert, Lara Joubert, Marie-Laure Curchod, Catherine Salvat, Isabelle Foucault, Catherine Jorand-Lebrun, Marc Lamarine, Hélène Peixoto, Chloé Vignaud, Christèle Frémaux, Thérèse Jomotte, Bernard Françon, Chantal Alliod, Lilia Bernasconi, Hadi Abderrahim, Dominique Perrin, Agnes Bombrun, Francisca Zanoguera, Christian Rommel,{ddagger} and Rob Hooft van Huijsduijnen*

Merck Serono SA, 1211 Geneva, Switzerland

Received 29 August 2008/ Returned for modification 11 December 2008/ Accepted 22 December 2008

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.

* Corresponding author. Mailing address: Merck Serono S.A., 9, Chemin des Mines, 1211 Geneva, Switzerland. Phone: 41 22 4143000. Fax: 41 22 7946965. E-mail: rob.hooft{at}merckserono.net

{triangledown} Published ahead of print on 12 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Intellikine, Inc., 10931 North Torrey Pines Road, La Jolla, CA 92037.

Molecular and Cellular Biology, March 2009, p. 1538-1553, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01375-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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