VOOZH about

URL: https://www.nature.com/articles/nn1995?error=cookies_not_supported&code=588d22b7-28b9-44f6-9e71-75c3c20d1945

⇱ Dissecting demyelination | Nature Neuroscience

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Abstract

The loss of central nervous system myelin and the failure of remyelination by oligodendrocytes contribute to the functional impairment that characterizes diseases such as multiple sclerosis. Why myelin repair fails in multiple sclerosis is currently unclear; however, new understanding of the generation of oligodendrocytes and myelination during development, as well as an increasing understanding of the bases of successful remyelination, are providing new insights and therapeutic targets. We propose that successful myelin repair of the adult CNS recapitulates a sequence of stages that generally correlate with those seen during development, whereas unsuccessful myelin repair results from the perturbation of a critical process in any one of several sequential events. Defining the rate-limiting steps and most vulnerable aspects at each stage of myelin repair will provide logical targets for therapeutic intervention in demyelinating diseases such as multiple sclerosis.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Myelination by oligodendrocytes in the CNS results from sequential series of events, each of which is regulated by several signals.

Similar content being viewed by others

References

  1. Reynolds, B.A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Rao, M.S., Noble, M. & Mayer-PrΓΆschel, M. A tripotential glial precursor cell is present in the developing spinal cord. Proc. Natl. Acad. Sci. USA 95, 3996–4001 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rowitch, D.H. Glial specification in the vertebrate neural tube. Nat. Rev. Neurosci. 5, 409–419 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Miller, R.H. Regulation of oligodendrocyte development in the vertebrate CNS. Prog. Neurobiol. 67, 451–467 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Miller, R.H. et al. Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4. J. Neurosci. Res. 76, 9–19 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Vallstedt, A., Klos, J.M. & Ericson, J. Multiple dorsoventral origins of oligodendrocyte generation in the spinal cord and hindbrain. Neuron 45, 55–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Cai, J. et al. Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6 regulation and Shh signaling. Neuron 45, 41–53 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Kessaris, N. et al. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat. Neurosci. 9, 173–179 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Chandran, S. et al. FGF dependent generation of oligodendrocyte by a hedgehog-independent pathway. Development 130, 6599–6609 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Noble, M., Murray, K., Stroobant, P., Waterfield, M.D. & Riddle, P. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333, 560–562 (1988).

    Article  CAS  PubMed  Google Scholar 

  11. Tsai, H.-H., Tessier-Lavinge, M. & Miller, R.H. Netrin I mediates spinal cord oligodendrocyte precursor dispersal. Development 130, 2095–2105 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Jarjour, A.A. et al. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord. J. Neurosci. 23, 3735–7344 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tsai, H.-H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Padovani-Claudio, D.A., Lui, L., Ransohoff, R.M. & Miller, R.H. Alterations in the oligodendrocyte lineage, myelin and white matter in adult mice lacking the chemokine receptor CXCR2. Glia 54, 471–483 (2006).

    Article  PubMed  Google Scholar 

  15. Calver, A.R. et al. Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20, 869–882 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. van Heyningen, P., Calver, A.R. & Richardson, W.D. Control of progenitor cell number by mitogen supply and demand. Curr. Biol. 11, 232–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci. 8, 745–751 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7, 221–228 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Charles, P. et al. Negative regulation of central nervous system myelination by polysialic acid adhesion molecule. Proc. Natl. Acad. Sci. USA 97, 7585–7590 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63–75 (1998).

    Article  PubMed  Google Scholar 

  21. Woodruff, R.H., Fruttiger, M., Richardson, W. & Franklin, R.M. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in the adult CNS and their response to following CNS demyelination. Mol. Cell. Neurosci. 25, 252–262 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Waubant, E. Biomarkers indicative of blood brain barrier disruption in multiple sclerosis. Dis. Markers 22, 235–244 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Franklin, R.J.M. Why does remyelination fail in multiple sclerosis? Nat. Rev. Neurosci. 3, 705–714 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. CΓ’mara, J. & ffrench-Constant, C. Lessons from oligodendrocyte biology on promoting repair in multiple sclerosis. J. Neurol. 254, 15–22 (2007).

    Article  CAS  Google Scholar 

  25. Hinks, G.L. & Franklin, R.J.M. Distinctive patterns of PDGF-A, FGF-2, IGF-1 and TGF-Ξ²1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Mol. Cell. Neurosci. 14, 153–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Fuller, M.L. et al. Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann. Neurol. 62, 288–300 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Huang, J.K. et al. Glial membranes at the node of Ranvier prevent neurite outgrowth. Science 310, 1813–1817 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Patrikios, P. et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129, 3165–3172 (2006).

    Article  PubMed  Google Scholar 

  29. Wolswijk, G. & Noble, M. Identification of an adult-specific glial progenitor cell. Development 105, 387–400 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Penderis, J., Shields, S.A. & Franklin, R.J. Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal existing in the rate central nervous system. Brain 126, 1382–1391 (2003).

    Article  PubMed  Google Scholar 

  31. Omari, K.M., John, G., Lango, R. & Raine, C.S. Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 53, 24–31 (2006).

    Article  PubMed  Google Scholar 

  32. Omari, K.M., John, G.R., Sealfon, S.C. & Raine, C.S. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain 128, 1003–1015 (2005).

    Article  PubMed  Google Scholar 

  33. Chang, A., Tourtellotte, W.W., Rudick, R. & Trapp, B.D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    Article  PubMed  Google Scholar 

  34. Trapp, B.D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Keyoung, H.M. & Goldman, S.A. Glial progenitor-based repair of demyelinating neurological diseases. Neurosurg. Clin. N. Am. 18, 93–104 (2007).

    Article  PubMed  Google Scholar 

  36. Groves, A.K. et al. Repair of demyelinated lesions by transplantation of purified O-2A progenitors. Nature 362, 453–455 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Woodhoo, A. et al. Schwann cell precursors: a favorable cell for myelin repair in the central nervous system. Brain 130, 2175–2185 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Pluchino, S. et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436, 266–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Nait-Oumesmar, B. et al. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur. J. Neurosci. 11, 4357–4366 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Lachapelle, F. et al. Failure of remyelination in the nonhuman primate optic nerve. Brain Pathol. 15, 198–207 (2005).

    Article  PubMed  Google Scholar 

  43. Bambakidis, N.C. & Miller, R.H. Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cord of adult rats after contusion. Spine J. 4, 16–26 (2004).

    Article  PubMed  Google Scholar 

  44. Bambakidis, N.C., Wang, R.-Z., Franic, L. & Miller, R.H. Sonic Hedgehog induces neural precursor proliferation after adult rodent spinal cord injury. J. Neurosurg. 99, 70–75 (2003).

    PubMed  Google Scholar 

  45. Gomes, W.A., Mehler, M. & Kessler, J. Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev. Biol. 255, 164–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Setoguchi, T. et al. Traumatic injury-induced BMP7 expression in the adult rat spinal cord. Brain Res. 921, 219–225 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Enzmann, G.U. et al. Consequences of noggin expression by neural stem, glial and neuronal precursor cells engrafted into the injured spinal cord. Exp. Neurol. 195, 293–304 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Kiernan, B.W., GΓΆtz, B., Fassner, A. & ffrench-Constant, C. Tenascin-C inhibits oligodendrocyte precursor cell migration by both adhesion-dependent and adhesion-independent mechanisms. Mol. Cell. Neurosci. 7, 322–335 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Rutishauser, U. Polysialic acid and the regulation of cell interactions. Curr. Opin. Cell Biol. 8, 679–684 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Lee, X. et al. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation. J. Neurosci. 27, 220–225 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank our colleagues for helpful comments. Parts of this work were supported by grants from the US National Institutes of Health (NS36674 and NS31800) and the Myelin Repair Foundation to R.H.M.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Center for Translational Neuroscience, 10900 Euclid Avenue, Case Western Reserve University, Cleveland, 44106, Ohio, USA

    Robert H Miller

  2. Department of Discovery Biology, Biogen Idec, 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Sha Mi

Authors
  1. Robert H Miller
  2. Sha Mi

Corresponding author

Correspondence to Robert H Miller.

About this article

Cite this article

Miller, R., Mi, S. Dissecting demyelination. Nat Neurosci 10, 1351–1354 (2007). https://doi.org/10.1038/nn1995

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nn1995

This article is cited by

Search

Advanced search

Quick links

πŸ‘ Nature Briefing

Sign up for the Nature Briefing newsletter β€” what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing