Convergent functional genomics of oligodendrocyte differentiation identifies multiple autoinhibitory signaling circuits
| Autor: | Dominique Perrin, Lara Joubert, Catherine Salvat, Isabelle Foucault, Bernard Françon, Hadi Abderrahim, Marc Lamarine, Catherine Jorand-Lebrun, Francisca Zanoguera, Rosanna Pescini Gobert, Marie Laure Curchod, Helene Peixoto, Agnes Bombrun, Lilia Bernasconi, Christian Rommel, Chantal Alliod, Rob Hooft van Huijsduijnen, Chloé Vignaud, Thérèse Jomotte, Christèle Frémaux |
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| Rok vydání: | 2009 |
| Předmět: |
Small interfering RNA
Cellular differentiation Neurogenesis Tretinoin Biology Dexamethasone Myelin Mice medicine Animals Gene Regulatory Networks Gene Silencing Remyelination Molecular Biology Cells Cultured Genetics Colforsin Oligodendrocyte differentiation Cell Differentiation Myelin Basic Protein Cell Biology Articles Oligodendrocyte Myelin basic protein Cell biology Rats Oligodendroglia medicine.anatomical_structure biology.protein Dual-Specificity Phosphatases Functional genomics Genome-Wide Association Study Signal Transduction |
| Zdroj: | Molecular and cellular biology. 29(6) |
| ISSN: | 1098-5549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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