Acta Neuropathologica

, Volume 134, Issue 3, pp 403–422 | Cite as

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)

References

  1. 1.
    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 CrossRefPubMedGoogle Scholar
  2. 2.
    Barres BA, Raff MC (1999) Axonal control of oligodendrocyte development. J Cell Biol 147:1123–1128CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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 CrossRefPubMedGoogle Scholar
  4. 4.
    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 51:135–146CrossRefPubMedGoogle Scholar
  5. 5.
    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 PubMedPubMedCentralGoogle Scholar
  6. 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
  7. 7.
    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 CrossRefPubMedGoogle Scholar
  8. 8.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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 CrossRefPubMedGoogle Scholar
  11. 11.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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 CrossRefPubMedGoogle Scholar
  13. 13.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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 CrossRefPubMedGoogle Scholar
  15. 15.
    Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855. doi:10.1038/nrn2480 CrossRefPubMedGoogle Scholar
  16. 16.
    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 CrossRefPubMedGoogle Scholar
  17. 17.
    Franklin RJ, Hinks GL (1999) Understanding CNS remyelination: clues from developmental and regeneration biology. J Neurosci Res 58:207–213CrossRefPubMedGoogle Scholar
  18. 18.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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 280:1610–1613CrossRefPubMedGoogle Scholar
  24. 24.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. doi:10.1093/brain/awn080 CrossRefPubMedGoogle Scholar
  27. 27.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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
  29. 29.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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. 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
  33. 33.
    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 CrossRefPubMedGoogle Scholar
  34. 34.
    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 CrossRefPubMedGoogle Scholar
  35. 35.
    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 66:238–246CrossRefPubMedGoogle Scholar
  36. 36.
    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 CrossRefPubMedGoogle Scholar
  37. 37.
    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 CrossRefPubMedGoogle Scholar
  38. 38.
    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 CrossRefPubMedGoogle Scholar
  39. 39.
    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 128:4881–4890PubMedGoogle Scholar
  40. 40.
    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 CrossRefPubMedGoogle Scholar
  41. 41.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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 CrossRefPubMedGoogle Scholar
  43. 43.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–252. doi:10.1038/nature09614 CrossRefPubMedGoogle Scholar
  45. 45.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    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 CrossRefPubMedGoogle Scholar
  47. 47.
    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 CrossRefPubMedGoogle Scholar
  48. 48.
    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 CrossRefPubMedGoogle Scholar
  49. 49.
    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 CrossRefPubMedGoogle Scholar
  50. 50.
    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 61:489–503PubMedGoogle Scholar
  51. 51.
    Raine CS, Wu E (1993) Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52:199–204CrossRefPubMedGoogle Scholar
  52. 52.
    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 CrossRefPubMedGoogle Scholar
  53. 53.
    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 CrossRefPubMedGoogle Scholar
  54. 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
  55. 55.
    Smith KJ, Blakemore WF, Mcdonald WI (1979) Central remyelination restores secure conduction. Nature 280:395–396. doi:10.1038/280395a0 CrossRefPubMedGoogle Scholar
  56. 56.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    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 CrossRefPubMedGoogle Scholar
  58. 58.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26:2–10CrossRefPubMedGoogle Scholar
  60. 60.
    Wingerchuk DM, Weinshenker BG (2000) Multiple sclerosis: epidemiology, genetics, classification, natural history, and clinical outcome measures. Neuroimaging Clin N Am 10:611–624, viiPubMedGoogle Scholar
  61. 61.
    Wolswijk G (2002) Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125:338–349CrossRefPubMedGoogle Scholar
  62. 62.
    Wolswijk G (2000) Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 123(Pt 1):105–115CrossRefPubMedGoogle Scholar
  63. 63.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    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 CrossRefPubMedGoogle Scholar

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

Personalised recommendations