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.

  • Letter
  • Published:

Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation

Nature volume 417, pages 443–447 (2002)Cite this article

Abstract

Neuronal growth cones are guided to their targets by attractive and repulsive guidance cues1. In mammals, netrin-1 is a bifunctional cue, attracting some axons and repelling others2,3,4,5. Deleted in colorectal cancer (Dcc) is a receptor for netrin-1 that mediates its chemoattractive effect on commissural axons6,7, but the signalling mechanisms that transduce this effect are poorly understood. Here we show that Dcc activates mitogen-activated protein kinase (MAPK) signalling, by means of extracellular signal-regulated kinase (ERK)-1 and -2, on netrin-1 binding in both transfected cells and commissural neurons. This activation is associated with recruitment of ERK-1/2 to a Dcc receptor complex. Inhibition of ERK-1/2 antagonizes netrin-dependent axon outgrowth and orientation. Thus, activation of MAPK signalling through Dcc contributes to netrin signalling in axon growth and guidance.

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: Dcc induces ERK-1/2 activation on netrin-1 binding.
Figure 2: Interaction of Dcc with ERK-1/2 and MEK-1/2.
Figure 3: Netrin-1-induced ERK-1/2 activation occurs in commissural neurons.
Figure 4: ERK-1/2 inhibition blocks netrin-mediated outgrowth and turning.

Similar content being viewed by others

References

  1. Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996)

    Article  ADS  CAS  Google Scholar 

  2. Serafini, T. et al. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78, 409–424 (1994)

    Article  CAS  Google Scholar 

  3. Kennedy, T. E., Serafini, T., de la Torre, J. R. & Tessier-Lavigne, M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78, 425–435 (1994)

    Article  CAS  Google Scholar 

  4. Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996)

    Article  CAS  Google Scholar 

  5. Hong, K. et al. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97, 927–941 (1999)

    Article  CAS  Google Scholar 

  6. Keino-Masu, K. et al. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996)

    Article  CAS  Google Scholar 

  7. Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997)

    Article  ADS  CAS  Google Scholar 

  8. Corset, V. et al. Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature 407, 747–750 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Stein, E. & Tessier-Lavigne, M. Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 291, 1928–1938 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998)

    Article  ADS  CAS  Google Scholar 

  11. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001)

    Article  ADS  CAS  Google Scholar 

  12. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995)

    Article  CAS  Google Scholar 

  13. Garrington, T. P. & Johnson, G. L. Organization and regulation of mitogen-activated protein kinase signalling pathways. Curr. Opin. Cell Biol. 11, 211–218 (1999)

    Article  CAS  Google Scholar 

  14. Birkenkamp, K. U. et al. p38MAP kinase inhibitor SB203580 enhances nuclear factor-κB transcriptional activity by a non-specific effect upon the ERK pathway. Br. J. Pharmacol. 131, 99–107 (2000)

    Article  CAS  Google Scholar 

  15. de la Torre, J. R. et al. Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC. Neuron 19, 1211–1224 (1997)

    Article  CAS  Google Scholar 

  16. Stein, E., Zou, Y., Poo, M.-M. & Tessier-Lavigne, M. Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation. Science 291, 1976–1982 (2001)

    Article  ADS  CAS  Google Scholar 

  17. Fukuda, M. et al. Induction of neurite outgrowth by MAP kinase in PC12 cells. Oncogene 11, 239–244 (1995)

    CAS  PubMed  Google Scholar 

  18. Kolkova, K., Novitskaya, V., Pedersen, N., Berezin, V. & Bock, E. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J. Neurosci. 20, 2238–2246 (2000)

    Article  CAS  Google Scholar 

  19. Schmid, R. S. et al. NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. J. Neurobiol. 38, 542–558 (1999)

    Article  CAS  Google Scholar 

  20. Schmid, R. S., Pruitt, W. M. & Maness, P. F. A MAP kinase-signalling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. J. Neurosci. 20, 4177–4188 (2000)

    Article  CAS  Google Scholar 

  21. Yamashita, H., Avraham, S., Jiang, S., Dikic, I. & Avraham, H. The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells. J. Biol. Chem. 274, 15059–15065 (1999)

    Article  CAS  Google Scholar 

  22. Elowe, S., Holland, S. J., Kulkarni, S. & Pawson, T. Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol. Cell Biol. 21, 7429–7441 (2001)

    Article  CAS  Google Scholar 

  23. Miao, H. et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nature Cell Biol. 3, 527–530 (2001)

    Article  CAS  Google Scholar 

  24. Gundersen, G. G. & Cook, T. A. Microtubules and signal transduction. Curr. Opin. Cell Biol. 11, 81–94 (1999)

    Article  CAS  Google Scholar 

  25. Schaefer, A. W. et al. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J. Biol. Chem. 274, 37965–37973 (1999)

    Article  CAS  Google Scholar 

  26. Kamiguchi, H. & Lemmon, V. Recycling of the cell adhesion molecule L1 in axonal growth cones. J. Neurosci. 20, 3676–3686 (2000)

    Article  CAS  Google Scholar 

  27. Sgambato, V. et al. In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signalling pathway, in the adult rat brain. J. Neurosci. 18, 214–226 (1998)

    Article  CAS  Google Scholar 

  28. Campbell, D. S. & Holt, C. E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32, 1013–1026 (2001)

    Article  CAS  Google Scholar 

  29. Herbert, T. P., Tee, A. R. & Proud, C. G. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J. Biol. Chem. 277, 11591–11596 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Pouyssegur for reagents and discussions; V. Fafeur and E. Bloch-Gallego for providing reagents; C. Guix for technical assistance; and S. Dazy for preliminary observations on ERK-1/2 activation. This work was supported by the Ligue Contre le Cancer and the ARC (P.M.). L.P. is supported by a post-doctoral fellowship from the Ligue Contre le Cancer. E.S. is an Associate and M.T.-L. an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Christelle Forcet, Elke Stein and Marc Tessier-Lavigne: These authors contributed equally to this work

Authors and Affiliations

  1. Apoptosis/Differentiation Laboratory—label ‘La Ligue’—Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622, Villeurbanne, France

    Christelle Forcet, Laurent Pays, Véronique Corset, Fabien Llambi & Patrick Mehlen

  2. Department of Biological Sciences, Howard Hughes Medical Institute, Stanford, California, 94035-5020, USA

    Elke Stein & Marc Tessier-Lavigne

Authors
  1. Christelle Forcet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elke Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent Pays
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Véronique Corset
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabien Llambi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc Tessier-Lavigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patrick Mehlen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Mehlen.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests

Rights and permissions

Reprints and permissions

About this article

Cite this article

Forcet, C., Stein, E., Pays, L. et al. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature 417, 443–447 (2002). https://doi.org/10.1038/nature748

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature748

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

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