title: p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation.
abstract: The mechanisms preventing efficient remyelination in the adult mammalian central nervous system after demyelinating inflammatory diseases, such as multiple sclerosis, are largely unknown. Partial remyelination occurs in early disease stages, but repair capacity diminishes over time and with disease progression. We describe a potent candidate for the negative regulation of oligodendroglial differentiation that may underlie failure to remyelinate. The p57kip2 gene is dynamically regulated in the spinal cord during MOG-induced experimental autoimmune encephalomyelitis. Transient down-regulation indicated that it is a negative regulator of post-mitotic oligodendroglial differentiation. We then applied short hairpin RNA-mediated gene suppression to cultured oligodendroglial precursor cells and demonstrated that down-regulation of p57kip2 accelerates morphological maturation and promotes myelin expression. We also provide evidence that p57kip2 interacts with LIMK-1, implying that p57kip2 affects cytoskeletal dynamics during oligodendroglial maturation. These data suggest that sustained down-regulation of p57kip2 is important for oligodendroglial maturation and open perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade in multiple sclerosis.
authors.affiliation: Department of Neurology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Kremer
authors.forename: André
authors.initials: A
authors.lastname: Heinen
authors.forename: Janusz
authors.initials: J
authors.lastname: Jadasz
authors.forename: Peter
authors.initials: P
authors.lastname: Göttle
authors.forename: Kristin
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Philipp
authors.initials: P
authors.lastname: Zickler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jander
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Patrick
authors.initials: P
authors.lastname: Küry
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis* / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D054461:Lim Kinases / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57; D054461:Lim Kinases; C515894:Limk1 protein, rat