TY - JOUR T1 - Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling JF - The Journal of Neuroscience JO - J. Neurosci. SP - 906 LP - 919 DO - 10.1523/JNEUROSCI.1423-14.2015 VL - 35 IS - 3 AU - Peter Göttle AU - Jennifer K. Sabo AU - André Heinen AU - Gene Venables AU - Klintsy Torres AU - Nevena Tzekova AU - Carlos M. Parras AU - David Kremer AU - Hans-Peter Hartung AU - Holly S. Cate AU - Patrick Küry Y1 - 2015/01/21 UR - http://www.jneurosci.org/content/35/3/906.abstract N2 - 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. ER -