title: Dual specificity phosphatase 15 regulates Erk activation in Schwann cells.
abstract: Schwann cells and oligodendrocytes are the myelinating cells of the peripheral and central nervous system, respectively. Despite having different myelin components and different transcription factors driving their terminal differentiation there are shared molecular mechanisms between the two. Sox10 is one common transcription factor required for several steps in development of myelinating glia. However, other factors are divergent as Schwann cells need the transcription factor early growth response 2/Krox20 and oligodendrocytes require Myrf. Likewise, some signaling pathways, like the Erk1/2 kinases, are necessary in both cell types for proper myelination. Nonetheless, the molecular mechanisms that control this shared signaling pathway in myelinating cells remain only partially characterized. The hypothesis of this study is that signaling pathways that are similarly regulated in both Schwann cells and oligodendrocytes play central roles in coordinating the differentiation of myelinating glia. To address this hypothesis, we have used genome-wide binding data to identify a relatively small set of genes that are similarly regulated by Sox10 in myelinating glia. We chose one such gene encoding Dual specificity phosphatase 15 (Dusp15) for further analysis in Schwann cell signaling. RNA interference and gene deletion by genome editing in cultured RT4 and primary Schwann cells showed Dusp15 is necessary for full activation of Erk1/2 phosphorylation. In addition, we show that Dusp15 represses expression of several myelin genes, including myelin basic protein. The data shown here support a mechanism by which early growth response 2 activates myelin genes, but also induces a negative feedback loop through Dusp15 to limit over-expression of myelin genes.
authors.affiliation: Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: José F
authors.initials: JF
authors.lastname: Rodríguez-Molina
authors.affiliation: Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Camila
authors.initials: C
authors.lastname: Lopez-Anido
authors.affiliation: Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Ki H
authors.initials: KH
authors.lastname: Ma
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Chongyu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Olson
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Katharina N
authors.initials: KN
authors.lastname: Muth
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Weider
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: John
authors.initials: J
authors.lastname: Svaren
mesh_terms: D000818:Animals; D002460:Cell Line; D054637:Dual-Specificity Phosphatases / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D012583:Schwann Cells / Q000201:enzymology*
chemical_list: D054637:Dual-Specificity Phosphatases
keywords: Dusp15; MEK-Erk; Schwann; Sox10; myelin