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.

Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration

Abstract

Nogo has been identified as a component of the central nervous system (CNS) myelin that prevents axonal regeneration in the adult vertebrate CNS. Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes1. The acidic amino terminus of Nogo-A is detected at the cytosolic face of cellular membranes1 and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury2,3. Here we show that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension, but does not alter non-neuronal cell morphology. In contrast, a multivalent form of the N terminus of Nogo-A affects the morphology of both neurons and other cell types. Here we identify a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycophosphatidylinositol-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human CNS injury.

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: Comparison of Nogo domains.
Figure 2: Ligand-binding assay for axonal Nogo-66 receptors.
Figure 3: Nogo-66 binding to COS-7 cells expressing the Nogo-66 receptor.
Figure 4: Structure of Nogo-66 receptor.
Figure 5: Distribution of Nogo-66 receptor expression.
Figure 6: Nogo-66 receptor mediates growth-cone collapse by Nogo-66.

References

  1. 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 

  2. 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  PubMed  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Schwab, M. & Caroni, P. Oligodendrocytes and CNS myelin are non-permissive substrates for neurite growth and fibroblast spreading in vitro. J. Neurosci. 8, 2381– 2393 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Caroni, P. & Schwab, M. E. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. J. Cell Biol. 106, 1281–1288 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Flanagan, J. G. & Leder, P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell 63, 185–194 ( 1990).

    Article  CAS  PubMed  Google Scholar 

  7. Schnell, L. & Schwab, M. E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269– 272 (1990).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Buffo, A. et al. Application of neutralizing antibodies against NI-35/250 myelin-associated neurite growth inhibitory proteins to the adult rat cerebellum induces sprouting of uninjured Purkinje cell axons. J. Neurosci. 20, 2275–2286 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Thallmair, M. et al. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nature Neurosci. 1, 124–131 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  10. Nakamura, F., Tanaka, M., Takahashi, T., Kalb, R. G. & Strittmatter, S. M. Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Neuron 21, 1093–1100 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Goshima, Y., Nakamura, F., Strittmatter, P. & Strittmatter, S. M. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376, 509– 514 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. 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  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to S.M.S. from the NIH and the Christopher Reeve Paralysis Foundation. A.F. was an FCAR research fellow. S.M.S. is an Investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fournier, A., GrandPre, T. & Strittmatter, S. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration . Nature 409, 341–346 (2001). https://doi.org/10.1038/35053072

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35053072

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