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
Original Paper

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.

Keywords

Remyelination Multiple sclerosis MYRF Oligodendrocyte Cre-loxP 

Supplementary material

401_2017_1741_MOESM1_ESM.pdf (16.6 mb)
Supplementary material 1 (PDF 17000 kb)

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Greg J. Duncan
    • 1
    • 2
  • Jason R. Plemel
    • 6
  • Peggy Assinck
    • 1
    • 3
  • Sohrab B. Manesh
    • 1
    • 3
  • Fraser G. W. Muir
    • 1
    • 4
  • Ryan Hirata
    • 1
  • Matan Berson
    • 1
  • Jie Liu
    • 1
  • Michael Wegner
    • 8
  • Ben Emery
    • 9
    • 10
  • G. R. Wayne Moore
    • 1
    • 4
    • 7
  • Wolfram Tetzlaff
    • 1
    • 2
    • 5
  1. 1.International Collaboration on Repair Discoveries (ICORD)Blusson Spinal Cord CentreVancouverCanada
  2. 2.Department of ZoologyUniversity of British ColumbiaVancouverCanada
  3. 3.Graduate Program in NeuroscienceUniversity of British ColumbiaVancouverCanada
  4. 4.Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  5. 5.Department of SurgeryUniversity of British ColumbiaVancouverCanada
  6. 6.Department of Clinical NeurosciencesHotchkiss Brain Institute, University of CalgaryCalgaryCanada
  7. 7.Vancouver Hospital and Health Sciences CentreVancouverCanada
  8. 8.Institut für Biochemie, Emil-Fischer-ZentrumFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  9. 9.Jungers Center for Neurosciences Research, School of MedicineOregon Health and Science UniversityPortlandUSA
  10. 10.Department of Anatomy and NeuroscienceUniversity of MelbourneParkvilleAustralia

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