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.

Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth

Abstract

The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS)1,2. In addition to myelin-associated glycoprotein (MAG)3,4 and Nogo-A5,6,7, available evidence suggests the existence of additional inhibitors in CNS myelin8. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR)9 as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: GPI-anchored myelin component(s) induces growth cone collapse.
Figure 2: OMgp is a myelin-associated inhibitor.
Figure 3: The Nogo-66 receptor is an OMgp-binding protein.
Figure 4: NgR mediates OMgp-elicited growth cone collapse.

References

  1. Schwab, M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996)

    Article  CAS  Google Scholar 

  2. Horner, P. J. & Gage, F. H. Regenerating the damaged central nervous system. Nature 407, 963–970 (2000)

    Article  ADS  CAS  Google Scholar 

  3. McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994)

    Article  CAS  Google Scholar 

  4. Mukhopadhyay, G. et al. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767 (1994)

    Article  CAS  Google Scholar 

  5. Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000)

    Article  ADS  CAS  Google Scholar 

  6. GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Tessier-Lavigne, M. & Goodman, C. S. Perspectives: neurobiology. Regeneration in the Nogo zone. Science 287, 813–814 (2000)

    Article  CAS  Google Scholar 

  9. Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Luo, Y., Raible, D. & Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993)

    Article  CAS  Google Scholar 

  11. Mikol, D. D. & Stefansson, K. A phosphatidylinositol-linked peanut agglutinin-binding glycoprotein in central nervous system myelin and on oligodendrocytes. J. Cell Biol. 106, 1273–1279 (1988)

    Article  CAS  Google Scholar 

  12. Mikol, D. D., Gulcher, J. R. & Stefansson, K. The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J. Cell Biol. 110, 471–479 (1990)

    Article  CAS  Google Scholar 

  13. He, Z. & Tessier-Lavigne, M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90, 739–751 (1997)

    Article  CAS  Google Scholar 

  14. Habib, A. A. et al. Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J. Neurochem. 70, 1704–1711 (1998)

    Article  CAS  Google Scholar 

  15. Niederost, B. P., Zimmermann, D. R., Schwab, M. E. & Bandtlow, C. E. Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J. Neurosci. 19, 8979–8989 (1999)

    Article  CAS  Google Scholar 

  16. Spillmann, A. A., Bandtlow, C. E., Lottspeich, F., Keller, F. & Schwab, M. E. Identification and characterization of a bovine neurite growth inhibitor (bNI-220). J. Biol Chem. 273, 19283–19293 (1998)

    Article  CAS  Google Scholar 

  17. Flanagan, J. G. & Cheng, H. J. Alkaline phosphatase fusion proteins for molecular characterization and cloning of receptors and their ligands. Methods Enzymol. 327, 198–210 (2000)

    Article  CAS  Google Scholar 

  18. Liu, B. P. & Strittmatter, S. M. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr. Opin. Cell. Biol. 13, 619–626 (2001)

    Article  CAS  Google Scholar 

  19. Norton, W. T. & Poduslo, S. E. Myelination in rat brain: method of myelin isolation. J. Neurochem. 21, 749–757 (1973)

    Article  CAS  Google Scholar 

  20. Neve, R. L., Howe, J. R., Hong, S. & Kalb, R. G. Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using recombinant herpes simplex virus. Neuroscience 79, 435–447 (1997)

    Article  CAS  Google Scholar 

  21. Huang, D. W., McKerracher, L., Braun, P. E. & David, S. A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24, 639–647 (1999)

    Article  CAS  Google Scholar 

  22. Takahashi, T., Nakamura, F., Jin, Z., Kalb, R. G. & Strittmatter, S. M. Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nature Neurosci. 1, 487–493 (1998)

    Article  CAS  Google Scholar 

  23. Cohen-Cory, S. & Fraser, S. E. Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature 378, 192–196 (1995)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Habib and J. Flanagan for providing the anti-OMgp antibodies and the AP-5 plasmid, and M. Greenberg, X. He, D. Lowenstein and M. Tessier-Lavigne for reading the manuscript. This study was supported by the Alfred Sloan Foundation, the Burroughs Wellcome Fund, the EJLB Foundation, the International Spinal Research Trust, the John Merck Fund, the Klingenstein Fund, the Whitehall Foundation, and the National Institutes of Health (NIH). K.C.W. is a recipient of a Howard Hughes Predoctoral Fellowship. V.K. is supported by an NIH predoctoral training grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhigang He.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, K., Koprivica, V., Kim, J. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002). https://doi.org/10.1038/nature00867

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00867

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — 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