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:

Antagonism between extradenticle function and Hedgehog signalling in the developing limb

Nature volume 394, pages 196–200 (1998)Cite this article

Abstract

The Drosophila homeobox gene extradenticle (exd) encodes a highly conserved cofactor of Hox proteins1,2,3. exd activity is regulated post-translationally by a mechanism involving nuclear translocation4,5; only nuclear Exd protein is functional. The exd gene is required for patterning of the proximal region of the leg6,7, whereas patterning of the distal region requires signalling by the Wingless (Wg) and Decapentaplegic (Dpp)8,9 proteins, which are in turn activated by Hedgehog (Hh)10. Here we show that exd function and Dpp/Wg signalling are antagonistic and divide the leg into two mutually exclusive domains. In the proximal domain, exd activity prevents cells from responding to Dpp and Wg. Conversely, in the distal domain, exd function is suppressed by the Dpp/Wg response gene Distal-less (Dll), which prevents the nuclear transport of Exd. We also found that the product of a murine homologue of exd (Pbx1) is regulated at the subcellular level, and that its pattern of nuclear localization in the mouse limb resembles that of Exd in the Drosophila leg. These findings suggest that the division of the limb into two antagonistic domains, as defined by exd (Pbx1) function and Hh signalling, may be a general feature of limb development.

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: Subdivision of the leg primordium and the leg disc into two distinct domains.
Figure 2: Pbx1 expression in the mouse limb primordium.
Figure 3: Differential effects of exd function on omb, dac and Dll expression in the leg disc.
Figure 4: Dpp and Wg signalling and Exd subcellular localization.
Figure 5: Control of Exd subcellular localization by Dll.

Similar content being viewed by others

References

  1. Peifer, M. & Wieschaus, E. Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev. 4, 1209–1223 (1990).

    Article  CAS  Google Scholar 

  2. Rauskolb, C., Peifer, M. & Wieschaus, E. extradenticle, a regulator of homeotic gene activity, is a homolog of the homeobox-containing human proto-oncogene pbx-1. Cell 74, 1101–1112 (1993).

    Article  CAS  Google Scholar 

  3. Mann, R. & Chan, S. K. Extra specificity from extradenticle: the partnership between Hox and exd/Pbx homeodomain proteins. Trends Genet. 12, 258–262 (1996).

    Article  CAS  Google Scholar 

  4. Mann, R. & Abu-Shaar, M. Nuclear import of the homeodomain protein Extradenticle in response to Wg and Dpp signalling. Nature 383, 630–633 (1996).

    Article  ADS  CAS  Google Scholar 

  5. Aspland, S. E. & White, R. A. H. Nucleocytoplasmic localization of extradenticle protein is spatially regulated throughout development in Drosophila. Development 124, 741–747 (1997).

    PubMed  CAS  Google Scholar 

  6. González-Crespo, S. & Morata, G. Control of Drosophila adult pattern by extradenticle. Development 121, 2117–2125 (1995).

    PubMed  Google Scholar 

  7. Rauskolb, C., Smith, K. M., Peifer, M. & Wieschaus, E. extradenticle determines segmental identities throughout Drosophila development. Development 121, 3663–3673 (1995).

    PubMed  CAS  Google Scholar 

  8. Diaz-Benjumea, F. J., Cohen, B. & Cohen, S. M. Cell interaction between compartments establishes the proximal–distal axis of Drosophila legs. Nature 372, 175–179 (1994).

    Article  ADS  CAS  Google Scholar 

  9. Lecuit, T. & Cohen, S. M. Proximal–distal axis formation in the Drosophila leg. Nature 388, 139–145 (1997).

    Article  ADS  CAS  Google Scholar 

  10. Basler, K. & Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368, 208–214 (1994).

    Article  ADS  CAS  Google Scholar 

  11. Cohen, S. M. & Jürgens, G. Proximo-distal pattern formation in Drosophila: cell autonomous requirements for Distal-less gene activity in limb development. EMBO J. 8, 2045–2055 (1989).

    Article  CAS  Google Scholar 

  12. Cohen, B., Simcox, A. A. & Cohen, S. M. Allocation of the thoracic imaginal primordia in the Drosophila embryo. Development 117, 597–608 (1993).

    PubMed  CAS  Google Scholar 

  13. Goto, S. & Hayashi, S. Specification of the embryonic limb primordium by graded activity of Decapentaplegic. Development 124, 125–132 (1997).

    PubMed  CAS  Google Scholar 

  14. Mardon, G., Solomon, N. M. & Rubin, G. M. dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila. Development 120, 3473–3486 (1994).

    PubMed  CAS  Google Scholar 

  15. Grim, S. & Pflugfelder, G. O. Control of the gene optomotor-blind in Drosophila wing development by decapentaplegic and wingless. Science 271, 1601–1604 (1996).

    Article  ADS  Google Scholar 

  16. González-Crespo, S. & Morata, G. Genetic evidence for the subdivision of the arthropod limb into coxopodite and telopodite. Development 122, 3921–3928 (1996).

    PubMed  Google Scholar 

  17. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  ADS  CAS  Google Scholar 

  18. Monica, K., Galili, N., Nourse, J., Saltman, D. & Cleary, M. L. PBX2 and PBX3, new homeobox genes with extensive homology ot the human protooncogene PBX1. Mol. Cell. Biol. 11, 6149–6157 (1991).

    Article  CAS  Google Scholar 

  19. Brook, W. J. & Cohen, S. M. Antagonistic interactions between wingless and decapentaplegic responsible for dorsal-ventral pattern in the Drosophila leg. Science 273, 1373–1377 (1996).

    Article  ADS  CAS  Google Scholar 

  20. Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a Dpp morphogen gradient. Cell 85, 357–368 (1996).

    Article  CAS  Google Scholar 

  21. Rieckohf, G., Casares, F., Ryoo, H. D., Abu-Shaar, M. & Mann, R. Nuclear translocation of Extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell 91, 171–183 (1997).

    Article  Google Scholar 

  22. Penton, A. & Hoffman, F. M. Decapentaplegic restricts the domain of wingless during Drosophila limb patterning. Nature 382, 162–165 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Jiang, J. & Struhl, G. Complementary and mutually exclusive activities of Decapentaplegic and Wingless organize axial patterning during Drosophila leg development. Cell 86, 401–409 (1996).

    Article  CAS  Google Scholar 

  24. Cohen, S. M., Brönner, G., Küntter, F., Jürgens, G. & Jäckle, H. Distal-less encodes a homeodomain protein required for limb development in Drosophila. Nature 338, 432–434 (1989).

    Article  ADS  CAS  Google Scholar 

  25. Morata, G. & Ripoll, P. Minutes: Mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975).

    Article  CAS  Google Scholar 

  26. Zecca, M., Basler, K. & Struhl, G. Direct and long range action of a wingless morphogen gradient. Cell 87, 833–844 (1996).

    Article  CAS  Google Scholar 

  27. Fuse, N., Hirose, S. & Hayashi, S. Determination of wing cell fate by the escargot and snail genes in Drosophila. Development 122, 1059–1067 (1996).

    PubMed  CAS  Google Scholar 

  28. Torres, M., Gómez-Pardo, E., Dressler, G. R. & Gruss, P. Pax2 controls multiple steps of urogenital development. Development 121, 4057–4065 (1995).

    PubMed  CAS  Google Scholar 

  29. Vachon, G. et al. Homeotic genes of the bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less. Cell 71, 437–450 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Basler, S. Carroll, S. Cohen, G. Mardon, G. Pflugfelder and G. Struhl for fly stocks and antibodies; F. Casares, E. Sánchez-Herrero and I. Guerrero for comments on the manuscript; J. Casanova for critical help; and A. Bosch for help with the confocal microscope. This work was supported by the Dirección General de Investigación Científica y Técnica (G.M.), a Human Frontiers grant (G.M. and R.S.M.), an institutional grant of the Fundación Ramón Areces to the Centro de Biología Molecular, Institutional grants of the CSIC and Pharmacia-Upjohn to the Departamento de Immunologia y Oncologia, and an NIH grant to R.S.M., who is a scholar of the Leukemia Society of America.

Author information

Author notes

  1. Sergio González-Crespo

    Present address: Centre d'Investigació i Desenvolupament, CSIC, Jordi Girona 18-26, 08034, Barcelona, Spain

  2. Sergio González-Crespo, Muna Abu-Shaar, Miguel Torres and Carlos Martínez-A: These authors contributed equally to this work

Authors and Affiliations

  1. Centro de Biología Molecular, CSIC-UAM, Universidad Autónoma de Madrid, 28049, Madrid, Spain

    Sergio González-Crespo & Ginés Morata

  2. Department of Biochemistry and Molecular Biophysics, and Integrated Program in Cellular, Molecular & Biophysical Studies, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, 10032, New York, USA

    Muna Abu-Shaar & Richard S. Mann

  3. Departamento de Inmunología y Oncologia, Centro Nacional de Biotecnologia, Universidad Autónoma de Madrid, 28049, Madrid, Spain

    Miguel Torres & Carlos Martínez-A

Authors
  1. Sergio González-Crespo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muna Abu-Shaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miguel Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Martínez-A
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard S. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ginés Morata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ginés Morata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

González-Crespo, S., Abu-Shaar, M., Torres, M. et al. Antagonism between extradenticle function and Hedgehog signalling in the developing limb. Nature 394, 196–200 (1998). https://doi.org/10.1038/28197

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/28197

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