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.

  • Article
  • Published:

A p75NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein

Nature Neuroscience volume 5, pages 1302–1308 (2002)Cite this article

Abstract

Myelin-associated glycoprotein (MAG), an inhibitor of axon regeneration, binds with high affinity to the Nogo-66 receptor (NgR). Here we report that the p75 neurotrophin receptor (p75NTR) is a co-receptor of NgR for MAG signaling. In cultured human embryonic kidney (HEK) cells expressing NgR, p75NTR was required for MAG-induced intracellular Ca2+ elevation. Co-immunoprecipitation showed an association of NgR with p75NTR that can be disrupted by an antibody against p75NTR (NGFR5), and extensive coexpression was observed in the developing rat nervous system. Furthermore, NGFR5 abolished MAG-induced repulsive turning of Xenopus axonal growth cones and Ca2+ elevation, both in neurons and in NgR/p75NTR-expressing HEK cells. Thus we conclude that p75NTR is a co-receptor of NgR for MAG signaling and a potential therapeutic target for promoting nerve regeneration.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Calcium signals at the growth cone induced by an extracellular gradient of MAG.
Figure 2: The p75NTR mediates MAG-dependent Ca2+ signaling in HEK-293 cells.
Figure 3: Association of NgR with hp75NTR.
Figure 4: Nogo Receptor and p75NTR are coexpressed in the developing nervous system.
Figure 5: MAG-induced growth cone repulsion is abolished by the p75NTR antibody NGFR5.

Similar content being viewed by others

References

  1. Caroni, P. & Schwab, M.E. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96 (1988).

    Article  CAS  Google Scholar 

  2. Schwab, M.E. Repairing the injured spinal cord. Science 295, 1029–1031 (2002).

    Article  CAS  Google Scholar 

  3. Fournier, A.E. & Strittmatter, S.M. Repulsive factors and axon regeneration in the CNS. Curr. Opin. Neurobiol. 11, 89–94 (2001).

    Article  CAS  Google Scholar 

  4. 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 

  5. Mukhopadhyay, G., Doherty, P., Walsh, F.S., Crocker, P.R. & Filbin, M.T. A novel role for myelin-associated glycoprotein as an inhibitor of axon regeneration. Neuron 13, 757–767 (1994).

    Article  CAS  Google Scholar 

  6. 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  CAS  Google Scholar 

  7. 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  CAS  Google Scholar 

  8. Pham-Dinh, D. et al. Characterization and expression of the cDNA coding for the human myelin/oligodendrocyte glycoprotein. J. Neurochem. 63, 2353–2356 (1994).

    Article  CAS  Google Scholar 

  9. Wang, K.C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    Article  CAS  Google Scholar 

  10. Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002).

    Article  CAS  Google Scholar 

  11. Liu, B., Fournier, A., GrandPre, T. & Strittmatter, S.M. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193 (2002).

    Article  CAS  Google Scholar 

  12. 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  CAS  Google Scholar 

  13. Yamashita, T., Higuchi, H. & Tohyama, M. The p75 receptor tranduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570 (2002).

    Article  CAS  Google Scholar 

  14. Song, H.j. et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281, 1515–1518 (1998).

    Article  CAS  Google Scholar 

  15. Marano, N. et al. Purification and amino terminal sequencing of human melanoma nerve growth factor receptor. J. Neurochem. 48, 225–232 (1987).

    Article  CAS  Google Scholar 

  16. Song, H.-J. & Poo, M.-M. Sinal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363 (1999).

    Article  CAS  Google Scholar 

  17. Ming, G., Henley, J., Tessier-Lavigne, M., Song, H. & Poo, M. Electrical activity modulates growth cone guidance by diffusible factors. Neuron 29, 441–452 (2001).

    Article  CAS  Google Scholar 

  18. Bandtlow, C.E., Schmidt, M.F., Hassinger, T.D., Schwab, M.E. & Kater, S.B. Role of intracellular calcium in NI-35-evoked collapse of neuronal growth cones. Science 259, 80–83 (1993).

    Article  CAS  Google Scholar 

  19. Jiang, H. et al. Both p140(trk) and p75(NGFR) nerve growth factor receptors mediate nerve growth factor-stimulated calcium uptake. J. Biol. Chem. 272, 6835–6837 (1997).

    Article  CAS  Google Scholar 

  20. DeBellard, M.E., Tang, S., Mukhopadhyay, G., Shen, Y.J. & Filbin, M.T. Myelin-associated glycoprotein inhibits axonal regeneration from a variety of neurons via interaction with a sialoglycoprotein. Mol. Cell. Neurosci. 7, 89–101 (1996).

    Article  CAS  Google Scholar 

  21. Ming, G. et al. Phospholipase C-γ and Phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 23, 139–148 (1999).

    Article  CAS  Google Scholar 

  22. Lohof, A.M., Quillan, M., Dan, Y. & Poo, M.-M. Asymmetric modulation of cytosolic cAMP activity induces growth cone turning. J. Neurosci. 12, 1253–1261 (1992).

    Article  CAS  Google Scholar 

  23. Chao, M.V. et al. Gene transfer and molecular cloning of the human NGF receptor. Science 232, 518–521 (1986).

    Article  CAS  Google Scholar 

  24. Lee, R., Kermani, P., Teng, K.K. & Hempstead, B.L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001).

    Article  CAS  Google Scholar 

  25. Hempstead, B.L. The many faces of p75NTR. Curr. Opin. Neurobiol. 12, 260–267 (2002).

    Article  CAS  Google Scholar 

  26. Huang, E.J. & Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    Article  CAS  Google Scholar 

  27. Lee, K.F., Bachman, K., Landis, S. & Jaenisch, R. Dependence on p75 for innervation of some sympathetic targets. Science 263, 1447–1449 (1994).

    Article  CAS  Google Scholar 

  28. McQuillen, P.S., DeFreitas, M.F., Zada, G. & Shatz, C.J. A novel role for p75NTR in subplate growth cone complexity and visual thalamocortical innervation. J. Neurosci. 22, 3580–3593 (2002).

    Article  CAS  Google Scholar 

  29. Walsh, G.S., Krol, K.M. & Kawaja, M.D. Absence of the p75 neurotrophin receptor alters the pattern of sympathosensory sprouting in the trigeminal ganglia of mice overexpressing nerve growth factor. J. Neurosci. 19, 258–273 (1999).

    Article  CAS  Google Scholar 

  30. Yan, Q. & Johnson, E.M. Jr. An immunohistochemical study of the nerve growth factor receptor in developing rats. J. Neurosci. 8, 3481–3498 (1988).

    Article  CAS  Google Scholar 

  31. Wang, X. et al. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon- myelin and synaptic contact. J. Neurosci. 22, 5505–5515 (2002).

    Article  CAS  Google Scholar 

  32. Turnley, A.M. & Bartlett, P.F. MAG and MOG enhance neurite outgrowth of embryonic mouse spinal cord neurons. Neuroreport 9, 1987–1990 (1998).

    Article  CAS  Google Scholar 

  33. Cai, D., Shen, Y., De Bellard, M., Tang, S. & Filbin, M.T. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).

    Article  CAS  Google Scholar 

  34. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).

    Article  CAS  Google Scholar 

  35. Neumann, S., Bradke, F., Tessier-Lavigne, M. & Basbaum, A.I. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885–893 (2002).

    Article  CAS  Google Scholar 

  36. Song, H-j., Ming, G-l. & Poo, M.-M. Cyclic-AMP-induced switching in turning direction of nerve growth cones. Nature 388, 275–279 (1997).

    Article  CAS  Google Scholar 

  37. Wang, Q. & Zheng, J.Q. cAMP-mediated regulation of neurotrophin-induced collapse of nerve growth cones. J. Neurosci. 18, 4973–4984 (1998).

    Article  CAS  Google Scholar 

  38. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  Google Scholar 

  39. Dickson, B.J. Rho GTPases in growth cone guidance. Curr. Opin. Neurobiol. 11, 103–110 (2001).

    Article  CAS  Google Scholar 

  40. Lehmann, M. et al. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547 (1999).

    Article  CAS  Google Scholar 

  41. Wahl, S., Barth, H., Ciossek, T., Aktories, K. & Mueller, B.K. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J. Cell Biol. 149, 263–270 (2000).

    Article  CAS  Google Scholar 

  42. Kozma, R., Sarner, S., Ahmed, S. & Lim, L. Rho family GTPases and neuronal growth cone remodeling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol. Cell. Biol. 17, 1201–1211 (1997).

    Article  CAS  Google Scholar 

  43. Yamashita, T., Tucker, K.I. & Barde, Y.A. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).

    Article  CAS  Google Scholar 

  44. Casaccia-Bonnefil, P., Kong, H. & Chao, M.V. Neurotrophins: the biological paradox of survival factors eliciting apoptosis. Cell Death Differ. 5, 357–364 (1998).

    Article  CAS  Google Scholar 

  45. Tabti, N., Alder, J. & Poo, M.-m. in Culturing Nerve Cells (eds. Banker, G. & Goslin, K.) 237–260 (MIT Press, Cambridge, Massachusetts, 1998).

    Google Scholar 

  46. Spitzer, N.C. & Lamborghini, J.E. The development of the action potential mechanism of amphibian neurons isolated in culture. Proc. Natl. Acad. Sci. USA 73, 1641–1645 (1976).

    Article  CAS  Google Scholar 

  47. Hong, K., Nishiyama, M., Henley, J., Tessier-Lavigne, M. & Poo, M. Calcium signaling in the guidance of nerve growth by netrin-1. Nature 403, 93–98 (2000).

    Article  CAS  Google Scholar 

  48. Ming, G. et al. Adaptation in the chemotactic guidance of nerve growth cones. Nature 417, 411–418 (2002).

    Article  CAS  Google Scholar 

  49. Hutson, L.D. & Bothwell, M. Expression and function of Xenopus laevis p75(NTR) suggest evolution of developmental regulatory mechanisms. J. Neurobiol. 49, 79–98 (2001).

    Article  CAS  Google Scholar 

  50. Zheng, J.Q., Felder, M., Connor, J.A., & Poo, M.-M. Turning of nerve growth cones induced by neurotransmitters. Nature 368, 140–144 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Wang and Z.-g. He for gifts of human NgR-flag and MAG-Fc clones, and L.-W. Wu for technical assistance. This work was supported by grants from the National Institutes of Health (M.P. & M.B.), and S.W. and J.H. were supported by National Research Service Awards.

Author information

Author notes

  1. Scott T. Wong and John R. Henley: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Scott T. Wong, John R. Henley, Kuo-hua Huang & Mu-ming Poo

  2. Department of Physiology and Biophysics, University of Washington, Seattle, 98195, Washington, USA

    Kevin C. Kanning & Mark Bothwell

Authors
  1. Scott T. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John R. Henley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin C. Kanning
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kuo-hua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark Bothwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mu-ming Poo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mu-ming Poo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, S., Henley, J., Kanning, K. et al. A p75NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 5, 1302–1308 (2002). https://doi.org/10.1038/nn975

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn975

This article is cited by

Search

Advanced 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