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:

Twisted gastrulation is a conserved extracellular BMP antagonist

Nature volume 410, pages 479–483 (2001)Cite this article

Abstract

Bone morphogenetic protein (BMP) signalling regulates embryonic dorsal–ventral cell fate decisions in flies, frogs and fish1. BMP activity is controlled by several secreted factors including the antagonists chordin and short gastrulation (SOG)2,3. Here we show that a second secreted protein, Twisted gastrulation (Tsg)4, enhances the antagonistic activity of Sog/chordin. In Drosophila, visualization of BMP signalling using anti-phospho-Smad staining5 shows that the tsg and sog loss-of-function phenotypes are very similar. In S2 cells and imaginal discs, TSG and SOG together make a more effective inhibitor of BMP signalling than either of them alone. Blocking Tsg function in zebrafish with morpholino oligonucleotides causes ventralization similar to that produced by chordin mutants. Co-injection of sub-inhibitory levels of morpholines directed against both Tsg and chordin synergistically enhances the penetrance of the ventralized phenotype. We show that Tsgs from different species are functionally equivalent, and conclude that Tsg is a conserved protein that functions with SOG/chordin to antagonize BMP signalling.

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: Tsg and SOG synergistically inhibit DPP signalling.
Figure 2: Vertebrate Tsg enhances chordin's antagonist function.
Figure 3: Functional equivalence of Tsg proteins.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Data deposits

Zebrafish tsg1 is deposited in GenBank under accession number AF332096.

References

  1. Holley, S. A. & Ferguson, E. L. Fish are like flies are like frogs: conservation of dorsal–ventral patterning mechanisms. BioEssays 19, 281– 284 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Ferguson, E. L. & Anderson, K. V. Localized, enhancement and repression of the activity of the TGF-β family member, decapentaplegic, is necessary for dorsal–ventral pattern formation in the Drosophila embryo. Development 114, 583– 597 (1992).

    CAS  PubMed  Google Scholar 

  3. Piccolo, S., Sasai, Y., Lu, B. & De Robertis, E. M. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of Chd to BMP-4. Cell 86, 589– 598 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mason, E. D., Konrad, K. D., Webb, C. D. & Marsh, J. L. Dorsal midline fate in Drosophila embryos requires twisted gastrulation, a gene encoding a secreted protein related to human connective tissue growth factor. Genes Dev. 8, 1489– 1501 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Tanimoto, H., Itoh, S., ten Dijke, P. & Tabata, T. Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Mol. Cell 5, 59– 71 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Ray, R. P., Arora, K., Nüsslein-Volhard, C. & Gelbart, W. M. The control of cell fate along the dorsal–ventral axis of the Drosophila embryo. Development 113, 35– 54 (1991).

    CAS  PubMed  Google Scholar 

  7. Arora, K. & Nüsslein-Volhard, C. Altered mitotic domains reveal fate map changes in Drosophila embryos mutant for zygotic dorsoventral patterning genes. Development 114, 1003– 1024 (1992).

    CAS  PubMed  Google Scholar 

  8. Marques, G. et al. Production of a DPP activity gradient in the early Drosophila embryo through the opposing actions of the SOG and TLD proteins. Cell 91, 417– 26 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Yu, K. et al. Processing of the Drosophila Sog protein creates a novel BMP inhibitory activity. Development 127, 2143– 2154 (2000).

    CAS  PubMed  Google Scholar 

  10. Ashe, H. L., Mannervik, M. & Levine, M. Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo. Development 127, 3305– 3312 (2000).

    CAS  PubMed  Google Scholar 

  11. Ferguson, E. L. & Anderson, K. V. Decapentaplegic acts as a morphogen to organize dorsal–ventral pattern in the Drosophila embryo. Cell 71, 451– 461 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Wharton, K. A., Ray, R. P. & Gelbart, W. M. An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo. Development 117, 807– 822 (1993).

    CAS  PubMed  Google Scholar 

  13. Nasevicius, A. & Ekker, S. C. Effective targeted gene ‘Knockdown’ in zebrafish. Nature Genet. 26, 216– 220 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Hammerschmidt, M. et al. dino and mercedes, two genes regulating dorsal development in the zebrafish embryo. Development 123, 95– 102 (1996).

    CAS  PubMed  Google Scholar 

  15. Miller-Bertoglio, V. et al. Maternal and zygotic activity of the zebrafish ogon locus antagonizes BMP signaling. Dev. Biol. 214, 72– 86 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Fisher, S., Amacher, S. L. & Halpern, M. E. Loss of cerebum function ventralizes the zebrafish embryo. Development 124, 1301– 1311 (1997).

    CAS  PubMed  Google Scholar 

  17. Mullins, M. C. et al. Genes establishing dorsoventral pattern formation in the zebrafish embryo: the ventral specifying genes. Development 123, 81– 93 (1996).

    CAS  PubMed  Google Scholar 

  18. Kishimoto, Y., Lee, K. H., Zon, L., Hammerschmidt, M. & Schulte-Merker, S. The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124, 4457– 4466 (1997).

    CAS  PubMed  Google Scholar 

  19. Dick, A. et al. Essential role of Bmp7 (snailhouse) and its prodomain in dorsoventral patterning of the zebrafish embryo. Development 127, 343– 354 (2000).

    CAS  PubMed  Google Scholar 

  20. 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 

  21. Segal, D. & Gelbart, W. M. Shortvein, a new component of the decapentaplegic gene complex in Drosophila melanogaster. Genetics 109, 119– 143 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chang, C. et al. Twisted gastrulation can function as a BMP antagonist. Nature 410, 483– 487 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Scott, I. C. et al. Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling. Nature 410, 475– 476 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Oelgeschlager, M., Larrain, J., Geissert, D. & De Robertis, E. M. The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405, 757– 763 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Holley, S. A. et al. The Xenopus dorsalizing factor noggin ventralizes Drosophila embryos by preventing DPP from activating its receptor. Cell 86, 607– 617 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Ashe, H. L. & Levine, M. Local inhibition and long-range enhancement of Dpp signal transduction by Sog. Nature 398, 427– 431 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Hukriede, N. A. et al. Radiation hybrid mapping of the zebrafish genome. Proc. Natl Acad. Sci. USA 96, 9745– 9750 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cho, K. W., Blumberg, B., Steinbeisser, H. & De Robertis, E. M. Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid. Cell 67, 1111– 1120 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jowelt, T. Analysis of protein and gene expression. Methods Cell Biol. 59, 63– 85 (1999).

    Google Scholar 

  30. Haerry, T. E., Khalsa, O., O'Connor, M. B. & Wharton, K. A. Synergistic signaling by two BMP ligands through the SAX and TKV receptors controls wing growth and patterning in Drosophila. Development 125, 3977– 3987 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to K. Cho, D. Greenspan and A. Hemmati-Brivanlou for communication of results before publication and to E. De Robertis for comments on the manuscript. We thank M. Tsang at R&D systems for a gift of purified mouse chordin; D. Greenspan for purified mouse Tsg-C protein; J. Groppe for purified Dpp; P. ten Dijke for the gift of anti-phospho Mad; and E. De Robertis for the Xenopus Tsg cDNA clone. We also thank E. Hirsch for assistance with the mouse FISH analysis. This work was supported by NIH grants to J.L.M, M.B.O and S.C.E. O.S. was supported by Nippon Roche K.K. A.P. was supported by a training grant from the NIH. M.B.O. is an Associate Investigator for the Howard Hughes Medical Institute.

Author information

Author notes

  1. Jeffrey J. Ross, Osamu Shimmi, Hyon Kim, Spencer Hermanson and Stephen C. Ekker: These authors contributed equally to this work

Authors and Affiliations

  1. Departments of Genetics, Cell Biology and Development,

    Jeffrey J. Ross, Osamu Shimmi, Hyon Kim, Spencer Hermanson, Stephen C. Ekker & Michael B. O'Connor

  2. Howard Hughes Medical Institute,

    Jeffrey J. Ross & Michael B. O'Connor

  3. Department of Pediatrics,

    Anna Petryk

  4. The Arnold and Mabel Beckman Center for Transposon Research, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Hyon Kim, Spencer Hermanson & Stephen C. Ekker

  5. Department of Developmental and Cell Biology, University of California, Irvine, 92697, California, USA

    Peter Vilmos, Karin Gaudenz & J. Lawrence Marsh

Authors
  1. Jeffrey J. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Osamu Shimmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Vilmos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Petryk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karin Gaudenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Spencer Hermanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephen C. Ekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael B. O'Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. Lawrence Marsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael B. O'Connor or J. Lawrence Marsh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ross, J., Shimmi, O., Vilmos, P. et al. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410, 479–483 (2001). https://doi.org/10.1038/35068578

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35068578

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