Myelin regulatory factor drives remyelination in multiple sclerosis

Greg J. Duncan, Jason R. Plemel, Peggy Assinck, Sohrab B. Manesh, Fraser G.W. Muir, Ryan Hirata, Matan Berson, Jie Liu, Michael Wegner, Ben Emery, G. R.Wayne Moore, Wolfram Tetzlaff

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-20
Number of pages20
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jun 19 2017

Fingerprint

Oligodendroglia
Myelin Sheath
Multiple Sclerosis
Demyelinating Diseases
Transcription Factors
Corpus Callosum
Myelin Proteins
Lysophosphatidylcholines
Glutathione Transferase

Keywords

  • Cre-loxP
  • Multiple sclerosis
  • MYRF
  • Oligodendrocyte
  • Remyelination

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Duncan, G. J., Plemel, J. R., Assinck, P., Manesh, S. B., Muir, F. G. W., Hirata, R., ... Tetzlaff, W. (Accepted/In press). Myelin regulatory factor drives remyelination in multiple sclerosis. Acta Neuropathologica, 1-20. https://doi.org/10.1007/s00401-017-1741-7

Myelin regulatory factor drives remyelination in multiple sclerosis. / Duncan, Greg J.; Plemel, Jason R.; Assinck, Peggy; Manesh, Sohrab B.; Muir, Fraser G.W.; Hirata, Ryan; Berson, Matan; Liu, Jie; Wegner, Michael; Emery, Ben; Moore, G. R.Wayne; Tetzlaff, Wolfram.

In: Acta Neuropathologica, 19.06.2017, p. 1-20.

Research output: Contribution to journalArticle

Duncan, GJ, Plemel, JR, Assinck, P, Manesh, SB, Muir, FGW, Hirata, R, Berson, M, Liu, J, Wegner, M, Emery, B, Moore, GRW & Tetzlaff, W 2017, 'Myelin regulatory factor drives remyelination in multiple sclerosis', Acta Neuropathologica, pp. 1-20. https://doi.org/10.1007/s00401-017-1741-7
Duncan GJ, Plemel JR, Assinck P, Manesh SB, Muir FGW, Hirata R et al. Myelin regulatory factor drives remyelination in multiple sclerosis. Acta Neuropathologica. 2017 Jun 19;1-20. https://doi.org/10.1007/s00401-017-1741-7
Duncan, Greg J. ; Plemel, Jason R. ; Assinck, Peggy ; Manesh, Sohrab B. ; Muir, Fraser G.W. ; Hirata, Ryan ; Berson, Matan ; Liu, Jie ; Wegner, Michael ; Emery, Ben ; Moore, G. R.Wayne ; Tetzlaff, Wolfram. / Myelin regulatory factor drives remyelination in multiple sclerosis. In: Acta Neuropathologica. 2017 ; pp. 1-20.
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