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:

Boc is a receptor for sonic hedgehog in the guidance of commissural axons

Nature volume 444, pages 369–373 (2006)Cite this article

Abstract

In the spinal cord, sonic hedgehog (Shh) is secreted by the floor plate to control the generation of distinct classes of ventral neurons along the dorsoventral axis1. Genetic and in vitro studies have shown that Shh also later acts as a midline-derived chemoattractant for commissural axons2. However, the receptor(s) responsible for Shh attraction remain unknown. Here we show that two Robo-related proteins, Boc and Cdon, bind specifically to Shh and are therefore candidate receptors for the action of Shh as an axon guidance ligand. Boc is expressed by commissural neurons, and targeted disruption of Boc in mouse results in the misguidance of commissural axons towards the floor plate. RNA-interference-mediated knockdown of Boc impairs the ability of rat commissural axons to turn towards an ectopic source of Shh in vitro. Taken together, these data suggest that Boc is essential as a receptor for Shh in commissural axon 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: Boc is expressed by young commissural neurons undergoing axon guidance decisions in the spinal cord.
Figure 2: Aberrant axon targeting in Boc -/- but not Cdon -/- spinal cord.
Figure 3: Boc and Cdon bind directly to Shh.
Figure 4: Boc is required for commissural axons to respond to the chemoattractive effect of Shh.

Similar content being viewed by others

References

  1. Ericson, J., Muhr, J., Jessell, T. M. & Edlund, T. Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal axis of the neural tube. Int. J. Dev. Biol. 39, 809–816 (1995)

    CAS  PubMed  Google Scholar 

  2. Charron, F., Stein, E., Jeong, J., McMahon, A. P. & Tessier-Lavigne, M. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113, 11–23 (2003)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Charron, F. & Tessier-Lavigne, M. Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance. Development 132, 2251–2262 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. 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  PubMed  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. 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  PubMed  Google Scholar 

  9. Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129–134 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Kang, J. S., Mulieri, P. J., Hu, Y., Taliana, L. & Krauss, R. S. BOC, an Ig superfamily member, associates with CDO to positively regulate myogenic differentiation. EMBO J. 21, 114–124 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kang, J. S., Mulieri, P. J., Miller, C., Sassoon, D. A. & Krauss, R. S. CDO, a robo-related cell surface protein that mediates myogenic differentiation. J. Cell Biol. 143, 403–413 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mulieri, P. J., Okada, A., Sassoon, D. A., McConnell, S. K. & Krauss, R. S. Developmental expression pattern of the cdo gene. Dev. Dyn. 219, 40–49 (2000)

    Article  CAS  PubMed  Google Scholar 

  13. Mulieri, P. J., Kang, J. S., Sassoon, D. A. & Krauss, R. S. Expression of the boc gene during murine embryogenesis. Dev. Dyn. 223, 379–388 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. Connor, R. M., Allen, C. L., Devine, C. A., Claxton, C. & Key, B. BOC, brother of CDO, is a dorsoventral axon-guidance molecule in the embryonic vertebrate brain. J. Comp. Neurol. 485, 32–42 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. Cole, F. & Krauss, R. S. Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr. Biol. 13, 411–415 (2003)

    Article  CAS  PubMed  Google Scholar 

  16. Ming, J. E. & Muenke, M. Holoprosencephaly: from Homer to Hedgehog. Clin. Genet. 53, 155–163 (1998)

    Article  CAS  PubMed  Google Scholar 

  17. Muenke, M. & Beachy, P. A. Genetics of ventral forebrain development and holoprosencephaly. Curr. Opin. Genet. Dev. 10, 262–269 (2000)

    Article  CAS  PubMed  Google Scholar 

  18. Lum, L. et al. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039–2045 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Yao, S., Lum, L. & Beachy, P. The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125, 343–357 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, W., Kang, J. S., Cole, F., Yi, M. J. & Krauss, R. S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10, 657–665 (2006)

    Article  CAS  PubMed  Google Scholar 

  21. Tenzen, T. et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 10, 647–656 (2006)

    Article  CAS  PubMed  Google Scholar 

  22. Friedel, R. H. et al. Gene targeting using a promoterless gene trap vector (‘targeted trapping’) is an efficient method to mutate a large fraction of genes. Proc. Natl Acad. Sci. USA 102, 13188–13193 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sabatier, C. et al. The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117, 157–169 (2004)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Long, H. et al. Conserved roles for Slit and Robo proteins in midline commissural axon guidance. Neuron 42, 213–223 (2004)

    Article  CAS  PubMed  Google Scholar 

  26. Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M. & Tabin, C. J. Biochemical evidence that patched is the Hedgehog receptor. Nature 384, 176–179 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Cheng, H. J. & Flanagan, J. G. Cloning and characterization of RTK ligands using receptor-alkaline phosphatase fusion proteins. Methods Mol. Biol. 124, 313–334 (2001)

    CAS  PubMed  Google Scholar 

  29. Okada, A., Lansford, R., Weimann, J. M., Fraser, S. E. & McConnell, S. K. Imaging cells in the developing nervous system with retrovirus expressing modified green fluorescent protein. Exp. Neurol. 156, 394–406 (1999)

    Article  CAS  PubMed  Google Scholar 

  30. Mitchell, K. J. et al. Functional analysis of secreted and transmembrane proteins critical to mouse development. Nature Genet. 28, 241–249 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Luo, A. O’Reilly, M. Scott and K. Shen for critically reading the manuscript; C. Jolicoeur and H. Rayburn for the generation of chimaeric mice; C. Kaznowski for technical assistance; R. Krauss, J. Zhang, M. Scott, H. Tian and F. de Sauvage for discussions during early stages of the project; and T. Rando for supporting A.O. during the writing of the manuscript. This work was supported by grants from the National Institute of Mental Health and American Cancer Institute to A.O., the National Eye Institute to S.K.M., the National Institute of Mental Health to M.T.L. and S.K.M., and the Arnold and Mabel Beckman Foundation, the Fonds de Recherche en Santé du Québec (FRSQ), the Canadian Institutes of Health Research (CIHR) and the Peter Lougheed Medical Research Foundation to F.C.

Author information

Author notes

  1. Ami Okada

    Present address: Department of Neurology, Stanford University School of Medicine, Stanford, California, 94305, USA

  2. Ami Okada and Frédéric Charron: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Stanford University, California, 94305, Stanford, USA

    Ami Okada, Frédéric Charron, David S. Shin & Susan K. McConnell

  2. Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Quebec, H2W 1R7, Montreal, Canada

    Frédéric Charron, Steves Morin & Pierre J. Fabre

  3. Department of Medicine, University of Montreal, Quebec, Montreal, Canada

    Frédéric Charron & Pierre J. Fabre

  4. Genentech, Inc., South San Francisco, 1 DNA Way, California, 94080, USA

    Karen Wong & Marc Tessier-Lavigne

Authors
  1. Ami Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frédéric Charron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steves Morin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David S. Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pierre J. Fabre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc Tessier-Lavigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Susan K. McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ami Okada.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Figures 1–6 and Supplementary Methods (PDF 4841 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okada, A., Charron, F., Morin, S. et al. Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369–373 (2006). https://doi.org/10.1038/nature05246

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05246

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