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.

  • Brief Communication
  • Published:

Extraembryonic proteases regulate Nodal signalling during gastrulation

Nature Cell Biology volume 4, pages 981–985 (2002)Cite this article

Abstract

During gastrulation, a cascade of inductive tissue interactions converts pre-existing polarity in the mammalian embryo into antero-posterior pattern. This process is triggered by Nodal, a protein related to transforming growth factor-β (TFG-β) that is expressed in the epiblast and visceral endoderm, and its co-receptor Cripto, which is induced downstream of Nodal. Here we show that the proprotein convertases Spc1 and Spc4 (also known as Furin and Pace4, respectively) are expressed in adjacent extraembryonic ectoderm. They stimulate Nodal maturation after its secretion and are required in vivo for Nodal signalling. Embryo explants deprived of extraembryonic ectoderm phenocopy Spc1−/−; Spc4−/− double mutants in that endogenous Nodal fails to induce Cripto. But recombinant mature Nodal, unlike uncleaved precursor, can efficiently rescue Cripto expression. Cripto is also expressed in explants treated with bone morphogenetic protein 4 (BMP4). This indicates that Nodal may induce Cripto through both a signalling pathway in the embryo and induction of Bmp4 in the extraembryonic ectoderm. A lack of Spc1 and Spc4 affects both pathways because these proteases also stimulate induction of Bmp4.

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: Spc1 and Spc4 regulate mesendoderm and AVE formation.
Figure 2: Genes downstream of Nodal are downregulated in Spc1−/−;Spc4−/− embryos.
Figure 3: Maturation occurs after secretion and potentiates Nodal activity.
Figure 4: Regulation of Nodal signalling by extra-embryonic Spc1 and Spc4.

Similar content being viewed by others

References

  1. Beddington, R. S. & Robertson, E. J. Cell 96, 195–209 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Weber, R. J., Pedersen, R. A., Wianny, F., Evans, M. J. & Zernicka-Goetz, M. Development 126, 5591–5598 (1999).

    CAS  PubMed  Google Scholar 

  3. Brennan, J. et al. Nature 411, 965–969 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Liu, P. et al. Nature Genet. 22, 361–365 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Lawson, K. A. & Pedersen, R. A. Development 101, 627–652 (1987).

    CAS  PubMed  Google Scholar 

  6. Kinder, S. J. et al. Development 128, 3623–3634 (2001).

    CAS  PubMed  Google Scholar 

  7. Wei, Y. & Mikawa, T. Development 127, 87–96 (2000).

    CAS  PubMed  Google Scholar 

  8. Skromne, I. & Stern, C. D. Development 128, 2915–2927 (2001).

    CAS  PubMed  Google Scholar 

  9. Ang, S. L. et al. Development 122, 243–252 (1996).

    CAS  PubMed  Google Scholar 

  10. Ding, J. et al. Nature 395, 702–707 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Dono, R. et al. Development 118, 1157–1168 (1993).

    CAS  PubMed  Google Scholar 

  12. Saijoh, Y. et al. Mol. Cell 5, 35–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Yeo, C.-Y. & Whitman, M. Mol. Cell 7, 949–957 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. de Souza, F. S. & Niehrs, C. Cell Tissue Res. 300, 207–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Belo, J. A. et al. Mech. Dev. 68, 45–57 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Kimura, C. et al. Dev. Biol. 225, 304–321 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Perea-Gomez, A. et al. Development 128, 753–765 (2001).

    CAS  PubMed  Google Scholar 

  18. Constam, D. B. & Robertson, E. J. J. Cell Biol. 144, 139–149 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Constam, D. B., Calfon, M. & Robertson, E. J. J. Cell Biol. 134, 181–191 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Winnier, G., Blessing, M., Labosky, P. A. & Hogan, B. L. M. Genes Dev. 9, 2105–2116 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Thomsen, G. H. & Melton, D. A. Cell 74, 433–441 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Roebroek, A. J. M. et al. Development 125, 4863–4876 (1998).

    CAS  PubMed  Google Scholar 

  23. Constam, D. B. & Robertson, E. J. Genes Dev. 14, 1146–1155 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Varlet, I., Collignon, J. & Robertson, E. J. Development 124, 1033–1044 (1997).

    CAS  PubMed  Google Scholar 

  25. Hobbs, S., Jitrapakdee, S. & Wallace, J. C. Biochem. Biophys. Res. Commun. 252, 368–372 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Constam, D. B. & Robertson, E. J. Development 127, 245–254 (2000).

    CAS  PubMed  Google Scholar 

  27. Collignon, J., Varlet, I. & Robertson, E. J. Nature 381, 155–158 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Robertson and A. Grapin-Botton for comments on the manuscript; L. Bikoff for antiserum to Nodal; J. Christian for testing antibodies to BMP4; J. Rossant and A. Russ for Eomes cDNA; E. Säuberli and G. Badic Benedetto for histology; and P.-A. Christinet and his staff for animal care. This work was supported by a long term fellowship from the Human Frontier Science Program (J.A.L.), and a grant from the Swiss National Science Foundation (D.B.C.).

Author information

Authors and Affiliations

  1. Developmental Biology Group, Swiss Institute for Experimental Cancer Research (ISREC), Chemin des Boveresses 155, Epalinges, CH-1066, Switzerland

    Séverine Beck, J. Ann Le Good, Marcela Guzman, Nadav Ben Haim, Karine Roy, Friedrich Beermann & Daniel B. Constam

Authors
  1. Séverine Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Ann Le Good
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcela Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadav Ben Haim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karine Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Friedrich Beermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel B. Constam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel B. Constam.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beck, S., Le Good, J., Guzman, M. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nat Cell Biol 4, 981–985 (2002). https://doi.org/10.1038/ncb890

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb890

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