Myelin regulatory factor drives remyelination in multiple sclerosis
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.
KeywordsRemyelination Multiple sclerosis MYRF Oligodendrocyte Cre-loxP
The PDGFRα CreERT line used in this study was a generous gift of Dr. William Richardson. The NogoA antibody used in the study was a kindly provided by Dr. Martin Schwab. We also thank Dr. Terry Joe Sprinkle for the antibody to CNP. Yasaman Chaeichi, Phillip Chau, and Arash Samiei are acknowledged for their technical assistance with cryostat sectioning and confocal microscopy. The authors would like to thank Susan Shin for her help with electron microscopy sectioning and imaging. Michael J. Lee is acknowledged for his assistance with transgenic breeding and genotyping, and Vladimira Pavlova and Zahra Samadi-Bahrami for histological sectioning and immunofluorescence staining of human tissue. We also thank Dr. Brett Hilton for his critical reading and editing of this manuscript.
Compliance with ethical standards
All animal experiments were approved by the University of British Columbia Animal Care Committee, in accordance with the guidelines of the Canadian Council on Animal Care.
Conflict of interest
The authors declare that they have no competing interests.
This study was supported by operating grants from the Multiple Sclerosis Society of Canada (EGID 1763 and 2810) and the Canadian Institutes of Health Research (MOP-130475) to W.T.G.J.D. is supported by a Multiple Sclerosis Society of Canada Doctoral Scholarship. J.R.P. is supported Donna Joan Oxford Postdoctoral Fellowship Award from the Multiple Sclerosis Society of Canada and postdoctoral fellowship awards from CIHR, T. Chen Fong, and Alberta Initiatives Health Solutions. P.A. received a Frederick Banting and Charles Best Canadian Graduate Scholarship-Doctoral Award. S.B.M. and F.G.W.M. received a Multiple Sclerosis Society of Canada Masters’ studentship. M.W. holds a Deutsche Forschungsgemeinschaft Grant (We1326/11). B.E. is supported by a project grant from the National Multiple Sclerosis Society (RG5106A1/1) and a Warren Distinguished Scholar in Neuroscience Research chair. G.R.W.M. is supported by an operating grant from the Multiple Sclerosis Society of Canada (EGID 2295). W.T. holds the John and Penny Ryan British Columbia Leadership Chair in Spinal Cord Research.
- 6.Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278. doi: 10.1523/JNEUROSCI.4178-07.2008 CrossRefPubMedGoogle Scholar
- 28.Jeffries MA, Urbanek K, Torres L, Wendell SG, Rubio ME, Fyffe-Maricich SL (2016) ERK1/2 activation in preexisting oligodendrocytes of adult mice drives new myelin synthesis and enhanced CNS function. J Neurosci 36:9186–9200. doi: 10.1523/JNEUROSCI.1444-16.2016 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M et al (2012) Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci 32:12528–12542. doi: 10.1523/JNEUROSCI.1069-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T et al (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276. doi: 10.1016/S0002-9440(10)64537-3 CrossRefPubMedPubMedCentralGoogle Scholar
- 54.Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322. doi: 10.1002/(SICI)1097-4652(200003)182:3<311:AID-JCP1>3.0.CO;2-9 CrossRefPubMedGoogle Scholar