Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling
| Autor: | Jennifer K. Sabo, Peter Göttle, André Heinen, Nevena Tzekova, Hans-Peter Hartung, Patrick Küry, Klintsy J. Torres, Holly S. Cate, David Kremer, Gene Venables, Carlos Parras |
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| Rok vydání: | 2015 |
| Předmět: |
Multiple Sclerosis
Cellular differentiation Active Transport Cell Nucleus HES5 Biology Cerebellar Cortex Mice Myelin Precursor cell Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Rats Wistar Remyelination Nuclear export signal Cyclin-Dependent Kinase Inhibitor p57 Cells Cultured Myelin Sheath Cell Nucleus General Neuroscience Cyclin-Dependent Kinase 2 Lim Kinases Cell Differentiation Articles Rats Repressor Proteins Oligodendroglia Protein Transport Cell nucleus medicine.anatomical_structure Cerebellar cortex Neuroscience |
| Zdroj: | The Journal of Neuroscience. 35:906-919 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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. Thep57kip2gene 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 bothin vivoandin vitro. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelinationin 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. |
| Databáze: | OpenAIRE |
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