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:

Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein

Abstract

The Hedgehog signalling pathway is essential for the development of diverse tissues during embryogenesis1. Signalling is activated by binding of Hedgehog protein to the multipass membrane protein Patched (Ptc)2,3. We have now identified a novel component in the vertebrate signalling pathway, which we name Hip (for Hedgehog-interacting protein) because of its ability to bind Hedgehog proteins. Hip encodes a membrane glycoprotein that binds to all three mammalian Hedgehog proteins with an affinity comparable to that of Ptc-1. Hip-expressing cells are located next to cells that express each Hedgehog gene. Hip expression is induced by ectopic Hedgehog signalling and is lost in Hedgehog mutants. Thus, Hip, like Ptc-1, is a general transcriptional target of Hedgehog signalling. Overexpression of Hip in cartilage, where Indian hedgehog (Ihh) controls growth4, leads to a shortened skeleton that resembles that seen when Ihh function is lost (B. St-Jacques, M. Hammerschmidt & A.P.M., in preparation). Our findings support a model in which Hip attenuates Hedgehog signalling as a result of binding to Hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any Hedgehog signal.

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: Sequence analysis of the Hip cDNA.
Figure 2: Analysis of the Hip protein.
Figure 3: Expression of Hip during embryogenesis.
Figure 4: Expression of Hip transcripts in animals with ectopic or defective Hedgehog signalling.
Figure 5: Analysis of skeleton in animals overexpressing Hip in chondrocytes.

Similar content being viewed by others

References

  1. Hammerschmidt, M., Brook, A. & McMahon, A. P. The world according to hedgehog. Trends Genet. 13, 14–21 (1997).

    Article  CAS  Google Scholar 

  2. Tabin, C. J. & McMahon, A. P. Recent advances in Hedgehog signaling. Trends Cell Biol. 7, 442–446 (1997).

    Article  CAS  Google Scholar 

  3. Ingham, P. W. Transducing Hedgehog: the story so far. EMBO J. 17, 3505–3511 (1998).

    Article  CAS  Google Scholar 

  4. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996).

    Article  ADS  CAS  Google Scholar 

  5. Jessell, T. M. & Dodd, J. Floor plate-derived signals and the control of neural cell pattern in vertebrates. Harvey Lect. 86, 87–128 (1990).

    Google Scholar 

  6. Schwabe, J. W. R., Rodriguez-Esteban, C. & Izpisua Belmonte, J. C. Limbs are moving: where are they going? Trends Genet. 14, 229–235 (1998).

    Article  CAS  Google Scholar 

  7. Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).

    Article  CAS  Google Scholar 

  8. Bitgood, M. J., Shen, L. & McMahon, A. P. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr. Biol. 6, 298–304 (1996).

    Article  CAS  Google Scholar 

  9. Porter, J. A. et al. Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 86, 21–34 (1996).

    Article  CAS  Google Scholar 

  10. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

    Article  CAS  Google Scholar 

  11. Cheng, H. J. & Flanagan, J. G. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 79, 157–168 (1994).

    Article  CAS  Google Scholar 

  12. Yang, Y. et al. Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb. Development 124, 4393–4404 (1997).

    CAS  PubMed  Google Scholar 

  13. von Heijne, G. Protein targeting signals. Curr. Opin. Cell Biol. 2, 604–608 (1990).

    Article  CAS  Google Scholar 

  14. Muskavitch, M. A. & Hoffmann, F. M. Homologs of vertebrate growth factors in Drosophila melanogaster and other invertebrates. Curr. Top. Dev. Biol. 24, 289–328 (1990).

    Article  CAS  Google Scholar 

  15. Brown, D. D. et al. The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis. Proc. Natl Acad. Sci. USA 93, 1924–1929 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Schneider, D., Bruton, C. J. & Chater, K. F. Characterization of spaA, a Streptomyces coelicolor gene homologous to a gene involved in sensing starvation in Escherichia coli. Gene 177, 243–251 (1996).

    Article  CAS  Google Scholar 

  17. Sanicola, M. et al. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc. Natl Acad. Sci. USA 94, 6238–6243 (1997).

    Article  ADS  CAS  Google Scholar 

  18. Matlack, K. E., Mothes, W. & Rapoport, T. A. Protein translocation: tunnel vision. Cell 92, 381–390 (1998).

    Article  CAS  Google Scholar 

  19. 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  Google Scholar 

  20. 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  Google Scholar 

  21. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  Google Scholar 

  22. Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A. & Scott, M. P. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 10, 301–312 (1996).

    Article  CAS  Google Scholar 

  23. Epstein, D. J., Marti, E., Scott, M. P. & McMahon, A. P. Antagonizing cAMP-dependent protein kinase A in the dorsal CNS activates a conserved Sonic hedgehog signaling pathway. Development 122, 2885–2894 (1996).

    CAS  PubMed  Google Scholar 

  24. Nakata, K. et al. Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing alpha 1(IX) collagen chains with a central deletion. Proc. Natl Acad. Sci. USA 90, 2870–2874 (1993).

    Article  ADS  CAS  Google Scholar 

  25. Cheah, K. S., Lau, E. T., Au, P. K. & Tam, P. P. Expression of the mouse alpha 1(II) collagen gene is not restricted to cartilage during development. Development 111, 945–953 (1991).

    CAS  PubMed  Google Scholar 

  26. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, (1989)).

    Google Scholar 

  27. Hirokawa, T., Boon-Chieng, S. & Mitaku, S. SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics 14, 378–379 (1998).

    Article  CAS  Google Scholar 

  28. Wilkinson, D. G. & Nieto, M. A. Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol. 225, 361–373 (1993).

    Article  CAS  Google Scholar 

  29. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, (1994)).

    Google Scholar 

Download references

Acknowledgements

We thank H.-J. Cheng for advice on expression cloning, J.-L. Chen for help with sequencing, B. St-Jacques for Ihh mutant embryos, S. Lee, J. McMahon and M. Bitgood for performing in situ hybridization, N. Wu for pronuclear injection, D. Faria and B. Klumpar for histological section, M. Scott for the Patched-1 expression clone, B. Seed for pCD5IgG1 vector, Y. Yamada for the α1(II) collagen expression vector and M. Sanicola for the RETL1 clone, anti-RETL1 antibody and a protocol for PI–PLC cleavage. We thank past and present members of the McMahon lab for discussion and critical reading of the manuscript. P.-T.C. is a fellow of the Leukemia Society of America. This work was supported by a grant from the NINDS to A.P.M. The GenBank accession number for Hip is AF116865.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chuang, PT., McMahon, A. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999). https://doi.org/10.1038/17611

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/17611

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

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