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.

Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling

Abstract

Fibroblast growth factors (FGFs) are pleiotrophic growth factors that control cell proliferation, migration, differentiation and embryonic patterning1. During early zebrafish embryonic development, FGFs regulate dorsoventral patterning by controlling ventral bone morphogenetic protein (BMP) expression2,3. FGFs function by binding and activating high-affinity tyrosine kinase receptors4. FGF activity is negatively regulated by members of the Sprouty family, which antagonize Ras signalling induced by receptor tyrosine kinases3,5,6,7,8. On the basis of similarities in their expression patterns during embryonic development, we have identified five genes that define a synexpression group — fgf8, fgf3, sprouty2, sprouty4, as well as a novel gene, sef (similar expression to fgf genes). Sef encodes a conserved putative transmembrane protein that shares sequence similarities with the intracellular domain of the interleukin 17 receptor9. Here we show that in zebrafish, Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Structure of Sef and comparison of its expression pattern during embryogenesis with other members of the fgf8 synexpression group.
Figure 2: FGF signalling regulates sef expression.
Figure 3: Phenotypes of sef gain- and loss-of-function animals.
Figure 4: Sef rescues defects caused by Fgf8/Ras/Raf/MEK signalling.
Figure 5: Sef rescues cell-cleavage defects that result from Ras/MEK hyperactivity and prevents MAPK activation.

Accession codes

Accessions

GenBank/EMBL/DDBJ

Data deposits

  • Sequences of mouse and zebrafish sef cDNAs have been deposited in Genbank with accession numbers AF424804 and AF401232, respectively.

References

  1. Goldfarb, M. Cytokine Growth Factor Rev. 7, 311–325 (1996).

    CAS  Article  PubMed  Google Scholar 

  2. Fürthauer, M., Thisse, C. & Thisse, B. Development 124, 4253–4264 (1997).

    PubMed  Google Scholar 

  3. Fürthauer, M. Reifers, F. Brand, M. Thisse, B. & Thisse, C. Development 128, 2175–2186 (2001).

    PubMed  Google Scholar 

  4. Klint, P. & Claesson-Welsh, L. Front. Biosci. 4, D165–D177 (1999).

  5. Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y. & Krasnow, M. A. Cell 92, 253–263 (1998).

    CAS  Article  PubMed  Google Scholar 

  6. Casci, T., Vinos, J. & Freeman, M. Cell 96, 655–665 (1999).

    CAS  Article  PubMed  Google Scholar 

  7. Tefft, J. D. et al. Curr. Biol. 9, 219–222 (1999).

    CAS  Article  PubMed  Google Scholar 

  8. Minowada, G. et al. Development 126, 4465–4475 (1999).

    CAS  PubMed  Google Scholar 

  9. Yao, Z. et al. Immunity 6, 811–821 (1995).

    Article  Google Scholar 

  10. Reifers, F. et al. Development 125, 2381–2395 (1998).

    CAS  PubMed  Google Scholar 

  11. Mohammadi, M. et al. Science 276, 955–960 (1997).

    CAS  Article  PubMed  Google Scholar 

  12. Umbhauer, M., Penzo-Mendez, A., Clavilier, L., Boucaut, J., Riou, J. J. Cell Sci. 113, 2865–2875 (2000).

    CAS  PubMed  Google Scholar 

  13. Whitman, M. & Melton, D. A. Nature 357, 252–254 (1992).

    CAS  Article  PubMed  Google Scholar 

  14. Nasevicius, A. & Ekker, S. C. Nature Genet. 26, 216–220 (2000).

    CAS  Article  PubMed  Google Scholar 

  15. Mullins, M. C. et al. Development 123, 81–93 (1996).

    CAS  PubMed  Google Scholar 

  16. Kim, J. et al. Biochem. Biophys. Res. Commun. 250, 516–530 (1998).

    CAS  Article  PubMed  Google Scholar 

  17. Fabian, J. R., Morrison, D. K. & Daar, I. O. J. Cell Biol. 122, 645–652. (1993).

    CAS  Article  PubMed  Google Scholar 

  18. Umbhauer, M., Marshall, C. J., Mason, C. S., Old, R. W. & Smith, J. C. Nature 376, 58–62 (1995).

    CAS  Article  PubMed  Google Scholar 

  19. Wilson, S. I., Graziano, E., Harland, R., Jessell, T. M. & Edlund, T. Curr. Biol. 10, 421–429 (2000).

    CAS  Article  PubMed  Google Scholar 

  20. Schulte-Merker, S. & Smith, J. C. Curr. Biol. 5, 62–67 (1995).

    CAS  Article  PubMed  Google Scholar 

  21. Daar, I. et al. Science 253,74–76 (1991).

    CAS  Article  PubMed  Google Scholar 

  22. Gabay, L., Seger, R. & Shilo, B. Z. Science 277,1103–1106 (1997).

    CAS  Article  PubMed  Google Scholar 

  23. Roehl, H. & Nusslein-Volhard, C. Curr. Biol. 7, 503–507 (2001).

    Article  Google Scholar 

  24. Raible, F. & Brand, M. Mech. Dev. 107,105–117 (2001).

    CAS  Article  PubMed  Google Scholar 

  25. Kolch, W. Biochem. J. 351, 289–305 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Conlon, R. A. & Herrmann, B. G. Methods Enzymol. 225, 373–383 (1993).

    CAS  Article  PubMed  Google Scholar 

  27. Hofmann, K., Bucher, P., Falquet, L. & Bairoch, A. Nucleic Acids Res. 27, 215–219 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Thisse, C., Thisse, B., Halpern, M. E. & Postlethwait, J. H. Dev. Biol. 164, 420–429 (1994).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to I. Daar, G. R. Martin, J-F. Riou, J. Smith, M. Umbhauer and M. Whitman for providing constructs used in this study. We thank I. Dawid for fruitful discussion and sharing data prior to publication. We thank V. Heyer, M. Koch, C. Lan for technical assistance and O. Nkundwa for caring for the zebrafish. M.F. was funded by the Ministère de l'Enseignement Supérieur de la Recherche, the Ligue Nationale Contre le Cancer and the Centre National de la Recherche Scientifique. B.T., C.T. and S-L.A. were supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer the Ligue Nationale Contre le Cancer and the National Institute of Health (RO1 RR15402). W.L. was funded by a fellowship from INSERM.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine Thisse.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fürthauer, M., Lin, W., Ang, SL. et al. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nat Cell Biol 4, 170–174 (2002). https://doi.org/10.1038/ncb750

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb750

Further reading

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