Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach.
Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related in vivo and in vitro models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.
Merck Serono S.A., Geneva, Switzerland.
Fanny
F
Schmidt
Monique
M
van den Eijnden
Rosanna
R
Pescini Gobert
Gabriela P
GP
Saborio
Susanna
S
Carboni
Chantal
C
Alliod
Sandrine
S
Pouly
Susan M
SM
Staugaitis
Ranjan
R
Dutta
Bruce
B
Trapp
Rob
R
Hooft van Huijsduijnen
D000368:Aged; D000818:Animals; D001921:Brain / Q000201:enzymology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002531:Cerebellum / Q000201:enzymology; D054637:Dual-Specificity Phosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology; D005260:Female; D055785:Gene Knockdown Techniques; D023281:Genomics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000201:enzymology* / Q000502:physiology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D058305:Sorting Nexins / Q000737:chemistry / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology; D013379:Substrate Specificity; D059467:Transcriptome
C499048:MBP protein, human; D004676:Myelin Basic Protein; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C431150:SNX6 protein, human; D058305:Sorting Nexins; D020797:Receptor, Platelet-Derived Growth Factor beta; C473895:DUSP18 protein, human; D054637:Dual-Specificity Phosphatases