title: Oligodendroglial maturation is dependent on intracellular protein shuttling.
abstract: Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these cells and interfere with their cellular maturation. The p57kip2 gene encodes one such potent inhibitor of oligodendroglial differentiation and this study sheds light on the underlying mode of action. We found that subcellular distribution of the p57kip2 protein changed during differentiation of rat, mouse, and human oligodendroglial cells both in vivo and in vitro. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelination in vitro. In contrast, nuclear accumulation of p57kip2 resulted in blocked oligodendroglial differentiation. Experimental evidence suggests that the inhibitory role of p57kip2 depends on specific interactions with binding proteins such as LIMK-1, CDK2, Mash1, and Hes5 either by controlling their site of action or their activity. Because functional restoration in demyelinating diseases critically depends on the successful generation of oligodendroglial cells, a therapeutic need that is currently unmet, the regulatory mechanism described here might be of particular interest for identifying suitable drug targets and devising novel therapeutic approaches.
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Göttle
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, 3010 Victoria, Australia, and.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Sabo
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Heinen
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, 3010 Victoria, Australia, and.
authors.forename: Gene
authors.initials: G
authors.lastname: Venables
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Klintsy
authors.identifier: http://orcid.org/0000-0003-4231-4123
authors.initials: K
authors.lastname: Torres
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Nevena
authors.initials: N
authors.lastname: Tzekova
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Inserm U1127, 75013 Paris, France.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Parras
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Kremer
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, 3010 Victoria, Australia, and.
authors.forename: Holly S
authors.initials: HS
authors.lastname: Cate
authors.affiliation: Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany, kuery@uni-duesseldorf.de.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0002-2654-1126
authors.initials: P
authors.lastname: Küry
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051357:Cyclin-Dependent Kinase 2; D050761:Cyclin-Dependent Kinase Inhibitor p57; D054461:Lim Kinases; D012097:Repressor Proteins; C065500:ASCL1 protein, human; C077478:HES5 protein, human; C515892:LIMK1 protein, human
keywords: inhibitor; mode of action; myelin repair; nuclear export; p57kip2; regeneration