Myelin regulatory factor drives remyelination in multiple sclerosis
| Autor: | Greg J. Duncan, Peggy Assinck, Michael Wegner, G. R. Wayne Moore, Ryan Hirata, Ben Emery, Sohrab B. Manesh, Fraser G. W. Muir, Jason R. Plemel, Jie Liu, Wolfram Tetzlaff, Matan Berson |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Multiple Sclerosis Nogo Proteins Transcription Factors/genetics Biology Pathology and Forensic Medicine Corpus Callosum 03 medical and health sciences Cellular and Molecular Neuroscience Myelin Mice 0302 clinical medicine 2' 3'-Cyclic Nucleotide 3'-Phosphodiesterase Spinal Cord/metabolism 2' 3'-Cyclic Nucleotide 3'-Phosphodiesterase/metabolism medicine Animals Humans Nogo Proteins/metabolism Corpus Callosum/metabolism Remyelination Transcription factor Mice Knockout Multiple sclerosis Multiple Sclerosis/metabolism Myelin regulatory factor Human brain medicine.disease Phenotype Oligodendrocyte Oligodendroglia 030104 developmental biology medicine.anatomical_structure Oligodendroglia/metabolism Spinal Cord nervous system Remyelination/physiology Immunology Neurology (clinical) Neuroscience 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Duncan, G J, Plemel, J R, Assinck, P, Manesh, S B, Muir, F G W, Hirata, R, Berson, M, Liu, J, Wegner, M, Emery, B, Moore, G R W & Tetzlaff, W 2017, ' Myelin regulatory factor drives remyelination in multiple sclerosis ', Acta Neuropathologica, vol. 134, no. 3, pp. 403-422 . https://doi.org/10.1007/s00401-017-1741-7 |
| DOI: | 10.1007/s00401-017-1741-7 |
| Popis: | Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase π positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure. |
| Databáze: | OpenAIRE |
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