Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling

被引:33
作者
Goettle, Peter [1 ]
Sabo, Jennifer K. [2 ]
Heinen, Andre [1 ]
Venables, Gene [2 ]
Torres, Klintsy [1 ]
Tzekova, Nevena [1 ]
Parras, Carlos M. [3 ]
Kremer, David [1 ]
Hartung, Hans-Peter [1 ]
Cate, Holly S. [2 ]
Kuery, Patrick [1 ]
机构
[1] Univ Dusseldorf, Dept Neurol, Fac Med, D-40225 Dusseldorf, Germany
[2] Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3010, Australia
[3] Univ Paris 06, INSERM, Inst Cerveau & Moellepiniere, U1127, F-75013 Paris, France
基金
英国医学研究理事会;
关键词
inhibitor; mode of action; myelin repair; nuclear export; p57kip2; regeneration; MULTIPLE-SCLEROSIS; PROGENITOR CELLS; GENE-EXPRESSION; NUCLEAR EXPORT; SPINAL-CORD; DIFFERENTIATION; REMYELINATION; P57KIP2; LESIONS; BRAIN;
D O I
10.1523/JNEUROSCI.1423-14.2015
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 underlyingmodeof action. Wefound 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.
引用
收藏
页码:906 / 919
页数:14
相关论文
共 49 条
[1]   bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS [J].
Arnett, HA ;
Fancy, SPJ ;
Alberta, JA ;
Zhao, C ;
Plant, SR ;
Kaing, S ;
Raine, CS ;
Rowitch, DH ;
Franklin, RJM ;
Stiles, CD .
SCIENCE, 2004, 306 (5704) :2111-2115
[2]   N-WASP regulates extension of filopodia and processes by oligodendrocyte progenitors, oligodendrocytes, and Schwann cells - Implications for axon ensheathment at myelination [J].
Bacon, Claire ;
Lakics, Viktor ;
Machesky, Laura ;
Rumsby, Martin .
GLIA, 2007, 55 (08) :844-858
[3]  
BARRES BA, 1994, DEVELOPMENT, V120, P1097
[4]  
Bartel P. L., 1993, CELLULAR INTERACTION, P153
[5]   Getting more from the two-hybrid system: N-terminal fusions to LexA are efficient and sensitive baits for two-hybrid studies [J].
Beranger, F ;
Aresta, S ;
deGunzburg, J ;
Camonis, J .
NUCLEIC ACIDS RESEARCH, 1997, 25 (10) :2035-2036
[6]   CDK inhibitors: Cell cycle regulators and beyond [J].
Besson, Arnaud ;
Dowdy, Steven F. ;
Roberts, James M. .
DEVELOPMENTAL CELL, 2008, 14 (02) :159-169
[7]   FROM PRECURSORS TO MYELINATING OLIGODENDROCYTES: CONTRIBUTION OF INTRINSIC AND EXTRINSIC FACTORS TO WHITE MATTER PLASTICITY IN THE ADULT BRAIN [J].
Boulanger, J. J. ;
Messier, C. .
NEUROSCIENCE, 2014, 269 :343-366
[8]  
Boulikas Teni, 1993, Critical Reviews in Eukaryotic Gene Expression, V3, P193
[9]   Differential requirement of cyclin-dependent kinase 2 for oligodendrocyte progenitor cell proliferation and differentiation [J].
Caillava, Celine ;
Baron-Van Evercooren, Anne .
CELL DIVISION, 2012, 7
[10]   Cdk2 loss accelerates precursor differentiation and remyelination in the adult central nervous system [J].
Caillava, Celine ;
Vandenbosch, Renaud ;
Jablonska, Beata ;
Deboux, Cyrille ;
Spigoni, Giulia ;
Gallo, Vittorio ;
Malgrange, Brigitte ;
Baron-Van Evercooren, Anne .
JOURNAL OF CELL BIOLOGY, 2011, 193 (02) :397-407