title: Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes during CNS remyelination.
abstract: During normal brain development, axons are myelinated by mature oligodendrocytes (OLGs). Under pathological, demyelinating conditions within the central nervous system (CNS), axonal remyelination is only partially successful because oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated state resulting in a failure to generate myelinating OLGs. Tissue Transglutaminase (TG2) is a multifunctional enzyme, which amongst other functions, is involved in cell differentiation. Therefore, we hypothesized that TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates remyelination. In vivo studies, using the cuprizone model for de- and remyelination in TG2(-/-) and wild-type mice, showed that during remyelination expression of proteolipid protein mRNA, as a marker for remyelination, in the corpus callosum lags behind in TG2(-/-) mice resulting in less myelin formation and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies showed that rat OPCs express TG2 protein and activity which reduces when the cells have matured into OLGs. Furthermore, when TG2 activity is pharmacologically inhibited, the differentiation of OPCs into myelin-forming OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in remyelination of the CNS, probably through stimulating OPC differentiation into myelin-forming OLGs. Therefore, manipulating TG2 activity may represent an interesting new target for remyelination in demyelinating diseases.
authors.affiliation: VU University Medical Center, Neuroscience Campus Amsterdam, Department of Anatomy & Neurosciences, Amsterdam, The Netherlands.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Van Strien
authors.forename: Wia
authors.initials: W
authors.lastname: Baron
authors.forename: Erik N T P
authors.initials: EN
authors.lastname: Bakker
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: John G J M
authors.initials: JG
authors.lastname: Bol
authors.forename: John J P
authors.initials: JJ
authors.lastname: Brevé
authors.forename: Rob
authors.initials: R
authors.lastname: Binnekade
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Van Der Laarse
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drukarch
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Van Dam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003471:Cuprizone / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008929:Mitochondria, Heart / Q000201:enzymology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D004856:Postural Balance / Q000502:physiology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011510:Proteolipids / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011510:Proteolipids; D012333:RNA, Messenger; C000717609:Tgm2 protein, rat; D003471:Cuprizone; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein