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:

RGM and its receptor neogenin regulate neuronal survival

Nature Cell Biology volume 6, pages 749–755 (2004)Cite this article

Abstract

Repulsive guidance molecule (RGM) is an axon guidance protein that repels retinal axons upon activation of the neogenin receptor. To understand the functions of RGM–neogenin complexes in vivo, we used gene transfer technology to perturb their expression in the developing neural tube of chick embryos. Surprisingly, neogenin over-expression or RGM down-expression in the neural tube induces apoptosis. Neogenin pro-apoptotic activity in immortalized neuronal cells and in the neural tube is associated with the cleavage of its cytoplasmic domain by caspases. Thus neogenin is a dependence receptor inducing cell death in the absence of RGM, whereas the presence of RGM inhibits this effect.

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: RGM and Neogenin expression in early chick embryos.
Figure 2: Neogenin over-expression induces cell death in the neural tube.
Figure 5: Pro-apoptotic potential of neogenin mutants in vivo.
Figure 3: RGM downregulation induces cell death in vivo.
Figure 4: Neogenin is a dependence receptor.

Similar content being viewed by others

References

  1. Monnier, P.P. et al. RGM is a repulsive guidance molecule for retinal axons. Nature 419, 392–395 (2002).

    Article  CAS  Google Scholar 

  2. Hamburger, V. & Hamilton, H.L. A series of normal stages in the development of the chick embryo. J. Morph. 88, 49–92 (1951).

    Article  CAS  Google Scholar 

  3. Vielmetter, J., Kayyem, J.F., Roman, J.M. & Dreyer, W.J. Neogenin, an avian cell surface protein expressed during terminal neuronal differentiation, is closely related to the human tumor suppressor molecule deleted in colorectal cancer. J. Cell Biol. 127, 2009–2020 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Rajagopalan, S. et al. Neogenin mediates the action of repulsive guidance molecule. Nature Cell Biol. DOI:10.1038/ncb1156 (2004).

  6. Llambi, F., Causeret, F., Bloch-Gallego, E. & Mehlen, P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 20, 2715–2722 (2001).

    Article  CAS  Google Scholar 

  7. Thibert, C. et al. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301, 843–846 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Mehlen, P. & Bredesen, B.E. The dependence receptor hypothesis. Apoptosis 4, 37–49 (2003).

    Google Scholar 

  10. Katahira, T. & Nakamura, H. Gene silencing in chick embryos with a vector-based small interfering RNA system. Dev. Growth Differ. 45, 361–367 (2003).

    Article  CAS  Google Scholar 

  11. Bai, J. et al. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nature Neurosci. 6, 1277–1283 (2003).

    Article  CAS  Google Scholar 

  12. 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, 925–941 (1999).

    Article  Google Scholar 

  13. Cho, K.R. & Fearon, E.R. DCC: linking tumor suppressor genes and altered cell surface interactions in cancer? Curr. Opin. Genet. Dev. 5, 72–78 (1995).

    Article  CAS  Google Scholar 

  14. Thiebault, K. et al. The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment. Proc. Natl Acad. Sci. USA 100, 4173–4178 (2003).

    Article  CAS  Google Scholar 

  15. Zaidi, A.U. et al. Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. J. Neurosci. 21, 169–175 (2001).

    Article  CAS  Google Scholar 

  16. Srinivasan, K., Strickland, P., Valdes, A., Shin, G.C. & Hinck, L. Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis. Dev. Cell 4, 371–382 (2003).

    Article  CAS  Google Scholar 

  17. Gad, J.M., Keeling, S.L., Wilks, A.F., Tan, S.S. & Cooper, H.M. The expression patterns of guidance receptors, DCC and Neogenin, are spatially and temporally distinct throughout mouse embryogenesis. Dev. Biol. 192, 258–273 (1997).

    Article  CAS  Google Scholar 

  18. Niederkofler, V., Salie, R., Sigrist, M. & Arber, S. Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system. J. Neurosci. 24, 808–818 (2004).

    Article  CAS  Google Scholar 

  19. Matsunaga, E., Araki, I. & Nakamura, H. Pax6 defines the di-mesencephalic boundary by repressing En1 and Pax2. Development 127, 2357–2365 (2000).

    CAS  PubMed  Google Scholar 

  20. Hughes, S.H., Greenhouse, J.J., Petropoulos, C.J. & Sutrave, P. Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors. J. Virol. 61, 3004–3012 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fekete, D.M. & Cepko, C.L. Retroviral infection coupled with tissue transplantation limits gene transfer in the chicken embryo. Proc. Natl Acad. Sci. USA 90, 2350–2354 (1993).

    Article  CAS  Google Scholar 

  22. Funahashi, J.-i. et al. Role of Pax-5 in the regulation of a mid-hindbrain organizer's activity. Dev. Growth Differ. 41, 59–72 (1999).

    Article  CAS  Google Scholar 

  23. Bally-Cuif, L., Wassef, M. Ectopic induction and reorganization of Wnt-1 expression in quail/chick chimeras. Development 120, 3379–3394 (1994).

    CAS  PubMed  Google Scholar 

  24. Marillat, V. et al. Spatiotemporal expression patterns of slit and robo genes in the rat brain. J. Comp. Neurol. 442, 130–155 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

We thank E. Fearon, S. H. Hughes and G. S. Salvesen for reagents, and H. Nakamura for expression vectors and discussions. We also thank C. Guix for technical assistance. A.C. is supported by Retina France, the Schlumberger foundation and Association pour la Recherche sur le Cancer (ARC). P.M. is supported by the Ligue Contre le Cancer, the Schlumberger foundation and the National Institute of Health (NIH). This work is also supported by a grant from the N.I.H. to S.M.S and by a BioChance grant from the Bundesministerium für Bildung und Forschung to Migragen. S.T.D. is supported by a post-doctoral fellowship from the Schlumberger foundation, E.M. is a recipient of HFSP Long-Term Fellowship. S.M.S. is an investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

Author information

Authors and Affiliations

  1. UMR CNRS 7102, Université Paris 6, 9 Quai Saint Bernard, Paris, 75005, France

    Eiji Matsunaga & Alain Chédotal

  2. CNRS UMR 5534, Label 'la Ligue', University of Lyon, Villeurbanne, 69622, France

    Servane Tauszig-Delamasure & Patrick Mehlen

  3. MigraGen AG, Spemannstrasse 34, Tuebingen, D-72076, Germany

    Philippe P. Monnier & Bernhard K. Mueller

  4. Toronto Western Hospital, 399 Bathurst Street, Toronto, M5T258, ON, Canada

    Philippe P. Monnier

  5. Abbott GmbH & Co KG, Knollstrasse, Ludwigshafen, 67601, Germany

    Bernhard K. Mueller

  6. Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, CT, USA

    Stephen M. Strittmatter

Authors
  1. Eiji Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Servane Tauszig-Delamasure
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philippe P. Monnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernhard K. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen M. Strittmatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrick Mehlen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alain Chédotal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alain Chédotal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsunaga, E., Tauszig-Delamasure, S., Monnier, P. et al. RGM and its receptor neogenin regulate neuronal survival. Nat Cell Biol 6, 749–755 (2004). https://doi.org/10.1038/ncb1157

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1157

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