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:

LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex

Abstract

Axon regeneration in the adult CNS is prevented by inhibitors in myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.

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: LINGO-1, a novel nervous system-specific protein.
Figure 2: Expression of LINGO-1 in the rat nervous system.
Figure 3: LINGO-1 binds NgR1.
Figure 4: LINGO-1 interacts with NgR1 and p75.
Figure 5: NgR1, p75 and LINGO-1 expression activates RhoA and transduces an inhibitory signal for neurite outgrowth.
Figure 6: LINGO-1 is required for the inhibitory activities of myelin inhibitors.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

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  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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Liu, B.P., 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 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. Wang, K.C., Kim, J.A., Sivasankaran, R., Segal, R. & He, Z. P75 interacts with the Nogo receptor as a coreceptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    Article  CAS  Google Scholar 

  10. Song, H. & Poo, M. The cell biology of neuronal navigation. Nat. Cell Biol. 3, E81–88 (2001).

    Article  CAS  Google Scholar 

  11. Yamashita, T. & Tohyama, M. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat. Neurosci. 6, 461–467 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed Central  Google Scholar 

  14. Mueller, B.K. Growth cone guidance: first steps towards a deeper understanding. Annu. Rev. Neurosci. 22, 351–388 (1999).

    Article  CAS  Google Scholar 

  15. 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  PubMed Central  Google Scholar 

  16. Arcaro, A. The small GTP-binding protein Rac promotes the dissociation of gelsolin from actin filaments in neutrophils. J. Biol. Chem. 273, 805–813 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  PubMed Central  Google Scholar 

  19. Wong, S.T. et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat. Neurosci. 5, 1302–1308 (2002).

    Article  CAS  Google Scholar 

  20. Aguayo, A.J., David, S. & Bray, G.M. Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents. J. Exp. Biol. 95, 231–240 (1981).

    CAS  PubMed  Google Scholar 

  21. Chisholm, A. & Tessier-Lavigne, M. Conservation and divergence of axon guidance mechanisms. Curr. Opin. Neurobiol. 9, 603–615 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  22. Fawcett, J.W. Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system. Cell Tissue Res. 290, 371–377 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Hunt, D., Coffin, R.S. & Anderson, P.N. The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J. Neurocytol. 31, 93–120 (2002).

    Article  CAS  Google Scholar 

  25. Ivanisevic, L., Banerjee, K. & Saragovi, H.U. Differential cross-regulation of TrkA and TrkC tyrosine kinase receptors with p75. Oncogene 22, 5677–5685 (2003).

    Article  CAS  Google Scholar 

  26. Ricci, A. et al. Neurotrophin and neurotrophin receptor protein expression in the human lung. Am. J. Respir. Cell. Mol. Biol. 30, 12–19 (2003).

    Article  Google Scholar 

  27. Robinson, L.L., Townsend, J. & Anderson, R.A. The human fetal testis is a site of expression of neurotrophins and their receptors: regulation of the germ cell and peritubular cell population. J. Clin. Endocrinol. Metab. 88, 3943–3951 (2003).

    Article  CAS  Google Scholar 

  28. Chauhan, N.B. & Siegel, G.J. Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain. Neurochem. Int. 43, 225–233 (2003).

    Article  CAS  Google Scholar 

  29. Barton, W.A. et al. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. Embo J. 22, 3291–3302 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  30. Pignot, V. et al. Characterization of two novel proteins, NgRH1 and NgRH2, structurally and biochemically homologous to the Nogo-66 receptor. J. Neurochem. 85, 717–728 (2003).

    Article  CAS  Google Scholar 

  31. Takahashi, N., Takahashi, Y. & Putnam, F.W. Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum. Proc. Natl. Acad. Sci. USA 82, 1906–1910 (1985).

    Article  CAS  Google Scholar 

  32. Nguyen-Ba-Charvet, K.T. & Chedotal, A. Role of Slit proteins in the vertebrate brain. J. Physiol. [Paris] 96, 91–98 (2002).

    Article  CAS  Google Scholar 

  33. Kuja-Panula, J., Kiiltomaki, M., Yamashiro, T., Rouhiainen, A. & Rauvala, H. AMIGO, a transmembrane protein implicated in axon tract development, defines a novel protein family with leucine-rich repeats. J. Cell Biol. 160, 963–973 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  34. Ono, T., Sekino-Suzuki, N., Kikkawa, Y., Yonekawa, H. & Kawashima, S. Alivin 1, a novel neuronal activity-dependent gene, inhibits apoptosis and promotes survival of cerebellar granule neurons. J. Neurosci. 23, 5887–5896 (2003).

    Article  CAS  Google Scholar 

  35. Lin, J.C., Ho, W.H., Gurney, A. & Rosenthal, A. The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons. Nat. Neurosci. 6, 1270–1276 (2003).

    Article  CAS  Google Scholar 

  36. Ren, X.D., Kiosses, W.B. & Schwartz, M.A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. Embo J. 18, 578–585 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  37. Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000).

    Article  CAS  Google Scholar 

  38. 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 

Download references

Acknowledgements

We thank V. Jung for scientific discussions and for editing of the manuscript, and the Biogen Neurobiology group, especially D. Sah and D. Lee, for their support and input. We also thank S. Strittmatter for helpful discussions and for kindly providing the AP-Nogo-66 cell line.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sha Mi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mi, S., Lee, X., Shao, Z. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci 7, 221–228 (2004). https://doi.org/10.1038/nn1188

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1188

This article is cited by

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