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.
Similar content being viewed by others
References
Bai CB, Sun S, Roholt A, Benson E, Edberg D, Medicetty S et al (2016) A mouse model for testing remyelinating therapies. Exp Neurol 283:330–340. doi:10.1016/j.expneurol.2016.06.033
Barres BA, Raff MC (1999) Axonal control of oligodendrocyte development. J Cell Biol 147:1123–1128
Barres BA, Raff MC (1994) Control of oligodendrocyte number in the developing rat optic-nerve. Neuron 12:935–942. doi:10.1016/0896-6273(94)90305-0
Bo L, Mork S, Kong PA, Nyland H, Pardo CA, Trapp BD (1994) Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol 51:135–146
Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM et al (2013) MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. doi:10.1371/journal.pbio.1001625
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
Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173. doi:10.1056/NEJMoa010994
Charles P, Hernandez MP, Stankoff B, Aigrot MS, Colin C, Rougon G et al (2000) Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc Natl Acad Sci USA 97:7585–7590. doi:10.1073/pnas.100076197
Denk F, Ramer LM, Erskine EL, Nassar MA, Bogdanov Y, Signore M et al (2015) Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis. Acta Neuropathol Commun 3:74. doi:10.1186/s40478-015-0255-6
Emery B (2010) Transcriptional and post-transcriptional control of CNS myelination. Curr Opin Neurobiol 20:601–607. doi:10.1016/j.conb.2010.05.005
Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB et al (2009) Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138:172–185. doi:10.1016/j.cell.2009.04.031
Fancy SP, Chan JR, Baranzini SE, Franklin RJ, Rowitch DH (2011) Myelin regeneration: a recapitulation of development? Annu Rev Neurosci 34:21–43. doi:10.1146/annurev-neuro-061010-113629
Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE et al (2011) Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 14:1009–1016. doi:10.1038/nn.2855
Fancy SP, Kotter MR, Harrington EP, Huang JK, Zhao C, Rowitch DH et al (2010) Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp Neurol 225:18–23. doi:10.1016/j.expneurol.2009.12.020
Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855. doi:10.1038/nrn2480
Franklin RJ, ffrench-Constant C, Edgar JM, Smith KJ (2012) Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol 8:624–634. doi:10.1038/nrneurol.2012.200
Franklin RJ, Hinks GL (1999) Understanding CNS remyelination: clues from developmental and regeneration biology. J Neurosci Res 58:207–213
Freeman SA, Desmazieres A, Simonnet J, Gatta M, Pfeiffer F, Aigrot MS et al (2015) Acceleration of conduction velocity linked to clustering of nodal components precedes myelination. Proc Natl Acad Sci USA 112:E321–E328. doi:10.1073/pnas.1419099112
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M et al (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189. doi:10.1093/brain/awp070
Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I et al (2015) Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 78:710–721. doi:10.1002/ana.24497
Gautier HO, Evans KA, Volbracht K, James R, Sitnikov S, Lundgaard I et al (2015) Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. Nat Commun 6:8518. doi:10.1038/ncomms9518
Gonzalez GA, Hofer MP, Syed YA, Amaral AI, Rundle J, Rahman S et al (2016) Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system. Sci Rep 6:31599. doi:10.1038/srep31599
Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH et al (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613
Hines JH, Ravanelli AM, Schwindt R, Scott EK, Appel B (2015) Neuronal activity biases axon selection for myelination in vivo. Nat Neurosci 18:683–689. doi:10.1038/nn.3992
Hornig J, Frob F, Vogl MR, Hermans-Borgmeyer I, Tamm ER, Wegner M (2013) The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes. PLoS Genet 9:e1003907. doi:10.1371/journal.pgen.1003907
Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. doi:10.1093/brain/awn080
Ishii A, Furusho M, Dupree JL, Bansal R (2014) Role of ERK1/2 MAPK signaling in the maintenance of myelin and axonal integrity in the adult CNS. J Neurosci 34:16031–16045. doi:10.1523/JNEUROSCI.3360-14.2014
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
Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68:668–681. doi:10.1016/j.neuron.2010.09.009
Keough MB, Rogers JA, Zhang P, Jensen SK, Stephenson EL, Chen T et al (2016) An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat Commun 7:11312. doi:10.1038/ncomms11312
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
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
Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332. doi:10.1523/JNEUROSCI.2615-05.2006
Kuhlmann T, Miron V, Cuo Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131:1749–1758. doi:10.1093/brain/awn096
Kuhlmann T, Remington L, Maruschak B, Owens T, Bruck W (2007) Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neuropathol Exp Neurol 66:238–246
Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. doi:10.1093/brain/awh641
Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE et al (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 33:366–374. doi:10.1038/ng1095
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods 25:402–408. doi:10.1006/meth.2001.1262
Mathis C, Denisenko-Nehrbass N, Girault JA, Borrelli E (2001) Essential role of oligodendrocytes in the formation and maintenance of central nervous system nodal regions. Development 128:4881–4890
McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K et al (2014) Motor skill learning requires active central myelination. Science 346:318–322. doi:10.1126/science.1254960
Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218. doi:10.1038/nn.3469
Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L (2007) A global double-fluorescent Cre reporter mouse. Genesis 45:593–605. doi:10.1002/dvg.20335
Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC et al (2015) Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522:216–220. doi:10.1038/nature14335
Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–252. doi:10.1038/nature09614
Nguyen T, Mehta NR, Conant K, Kim KJ, Jones M, Calabresi PA et al (2009) Axonal protective effects of the myelin-associated glycoprotein. J Neurosci 29:630–637. doi:10.1523/JNEUROSCI.5204-08.2009
Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172. doi:10.1093/Brain/Awl217
Piaton G, Aigrot MS, Williams A, Moyon S, Tepavcevic V, Moutkine I et al (2011) Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain 134:1156–1167. doi:10.1093/brain/awr022
Plemel JR, Manesh SB, Sparling JS, Tetzlaff W (2013) Myelin inhibits oligodendroglial maturation and regulates oligodendrocytic transcription factor expression. Glia 61:1471–1487. doi:10.1002/Glia.22535
Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES (1993) Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33:137–151. doi:10.1002/ana.410330203
Prineas JW, Kwon EE, Goldenberg PZ, Ilyas AA, Quarles RH, Benjamins JA et al (1989) Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Investig 61:489–503
Raine CS, Wu E (1993) Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52:199–204
Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A et al (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–1401. doi:10.1038/nn.2220
Schneider S, Gruart A, Grade S, Zhang Y, Kroger S, Kirchhoff F et al (2016) Decrease in newly generated oligodendrocytes leads to motor dysfunctions and changed myelin structures that can be rescued by transplanted cells. Glia 64:2201–2218. doi:10.1002/glia.23055
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
Smith KJ, Blakemore WF, Mcdonald WI (1979) Central remyelination restores secure conduction. Nature 280:395–396. doi:10.1038/280395a0
Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM et al (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4. doi:10.1186/1471-213X-1-4
Stoffels JM, de Jonge JC, Stancic M, Nomden A, van Strien ME, Ma D et al (2013) Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain 136:116–131. doi:10.1093/brain/aws313
Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M et al (2002) Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 16:165–170. doi:10.1101/gad.215802
van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26:2–10
Wingerchuk DM, Weinshenker BG (2000) Multiple sclerosis: epidemiology, genetics, classification, natural history, and clinical outcome measures. Neuroimaging Clin N Am 10:611–624, vii
Wolswijk G (2002) Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125:338–349
Wolswijk G (2000) Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 123(Pt 1):105–115
Xiao L, Ohayon D, McKenzie IA, Sinclair-Wilson A, Wright JL, Fudge AD et al (2016) Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. Nat Neurosci 19:1210–1217. doi:10.1038/nn.4351
Yeung MSY, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159:766–774. doi:10.1016/j.cell.2014.10.011
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Funding
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Duncan, G.J., Plemel, J.R., Assinck, P. et al. Myelin regulatory factor drives remyelination in multiple sclerosis. Acta Neuropathol 134, 403–422 (2017). https://doi.org/10.1007/s00401-017-1741-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-017-1741-7