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The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals

Nature volume 397, pages 707–710 (1999)Cite this article

Abstract

Embryological and genetic evidence indicates that the vertebrate head is induced by a different set of signals from those that organize trunk–tail development1,2,3,4,5,6. The gene cerberus encodes a secreted protein that is expressed in anterior endoderm and has the unique property of inducing ectopic heads in the absence of trunk structures1. Here we show that the cerberus protein functions as a multivalent growth-factor antagonist in the extracellular space: it binds to Nodal, BMP and Wnt proteins via independent sites. The expression of cerberus during gastrulation is activated by earlier nodal-related signals in endoderm and by Spemann-organizer factors that repress signalling by BMP and Wnt. In order for the head territory to form, we propose that signals involved in trunk development, such as those involving BMP, Wnt and Nodal proteins, must be inhibited in rostral regions.

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Figure 1: Cerberus protein binds to Xnr-1, BMP-4 and Xwnt-8.
Figure 2: Phenotypic effects of cer-S mRNA, an inhibitor of nodal-related signals.
Figure 3: Head induction requires the triple inhibition of nodal-related, Wnt and BMP signals.
Figure 4

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References

  1. Bouwmeester, T., Kim, S. H., Sasai, Y., Lu, B. & De Robertis, E. M. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer. Nature 382, 595–601 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Thomas, P. & Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Shawlot, W. & Behringer, R. R. Requirement for Lim1 in head-organizer function. Nature 374, 425–430 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Glinka, A., Wu, W., Onichtchouk, D., Blumenstock, C. & Niehrs, C. Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus. Nature 389, 517–519 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Glinka, A. et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391, 357–362 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Harland, R. & Gerhart, J. Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Biol. 13, 611–667 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Hsu, D. R., Economides, A. N., Wang, X., Eimon, P. M. & Harland, R. M. The Xenopus dorsalizing factor gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol. Cell 1, 673–683 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Belo, J. A. et al. Cerberus-like is a secreted factor with neuralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech. Dev. 68, 45–57 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Jones, C. M., Kuehn, M. R., Hogan, B. L. M., Smith, J. C. & Wright, C. V. E. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121, 3651–3662 (1995).

    CAS  PubMed  Google Scholar 

  10. Piccolo, S. et al. Cleavage of Chordin by Xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity. Cell 91, 407–416 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Feldman, B. et al. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395, 181–185 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Sampath, K. et al. Induction of the zebrafish ventral brain and floor plate requires cyclops/nodal signalling. Nature 395, 185–189 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Rebagliati, M. R., Toyama, R., Haffter, P. & Dawid, I. B. cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl Acad. Sci. USA 95, 9932–9937 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Varlet, I., Collignon, J. & Robertson, E. J. Nodal expression in the primitive endoderm is required for the specification of the anterior axis during mouse gastrulation. Development 124, 1033–1044 (1997).

    CAS  PubMed  Google Scholar 

  15. Conlon, F. L. et al. Aprimary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919–1928 (1994).

    CAS  PubMed  Google Scholar 

  16. Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L. & Robertson, E. J. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92, 797–808 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Nomura, M. & Li, E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393, 786–790 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Chang, C., Wilson, P. A., Mathews, L. S. & Hemmati-Brivanlou, A. A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis. Development 124, 827–837 (1997).

    CAS  PubMed  Google Scholar 

  19. Hoppler, S. & Moon, R. T. BMP-2/4 and Wnt-8 cooperatively pattern the Xenopus mesoderm. Mech Dev. 71, 119–129 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Leyns, L., Bouwmeester, T., Kim, S. H., Piccolo, S. & De Robertis, E. M. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann Organizer. Cell 88, 747–756 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rhinn, M. et al. Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification. Development 125, 845–856 (1998).

    CAS  PubMed  Google Scholar 

  22. Bouwmeester, T. & Leyns, L. Vertebrate head induction by anterior primitive endoderm. BioEssays 19, 855–863 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Henry, G. L. & Melton, D. A. Mixer, a homeobox gene required for endoderm development. Science 281, 91–96 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Kessler, D. S. & Melton, D. A. Induction of dorsal mesoderm by soluble, mature Vg1 protein. Development 121, 2155–2164 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. S. Mathews, N. Ueno, R. Moon, D. Melton and K. Cho for gifts of plasmids, K.Masuhara for anti-BMP4 mAb, Genetics Institute for BMPs, and members of the De Robertis laboratory for comments. S.P., E.A., S.B. and H.G were supported by Telethon, ARC, MSTP and DFG, respectively. This work was supported by a grant from the NIH. E.M.D.R. is a Howard Hughes Medical Institute investigator.

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Author notes

  1. Stefano Piccolo

    Present address: Istituto di Istologia ed Embriologia, Università di Padova, 35100, Padova, Italy

  2. Luc Leyns

    Present address: Vrije Universiteit Brussels, 1050, Brussels, Belgium

  3. Horst Grunz

    Present address: Abteilung Zoophysiologie, Universität GH Essen, 45117, Essen, Germany

  4. Stefano Piccolo and Eric Agius: These authors contributed equally to this work

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, 90095-1662, California, USA

    Stefano Piccolo, Eric Agius, Luc Leyns, Subha Bhattacharyya, Horst Grunz & E. M. De Robertis

  2. EMBL, Meyerhofstrasse 1, Heidelberg, 69117, Germany

    Tewis Bouwmeester

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Piccolo, S., Agius, E., Leyns, L. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397, 707–710 (1999). https://doi.org/10.1038/17820

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