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:

Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling

Nature volume 410, pages 475–478 (2001)Cite this article

An Erratum to this article was published on 01 June 2001

This article has been updated

Abstract

Twisted gastrulation (TSG) is involved in specifying the dorsal-most cell fate in Drosophila embryos1, but its mechanism of action is poorly understood. TSG has been proposed to modify the action of Short gastrulation (SOG), thereby increasing signalling by the bone morphogenetic protein (BMP) Decapentaplegic. SOG, an inhibitor of BMP signalling, is in turn inactivated by the protease Tolloid2,3. Here we identify Tsg gene products from human, mouse, Xenopus, zebrafish and chick. Expression patterns in mouse and Xenopus embryos are consistent with in vivo interactions between Tsg, BMPs and the vertebrate SOG orthologue, chordin. We show that Tsg binds both the vertebrate Decapentaplegic orthologue BMP4 and chordin, and that these interactions have multiple effects. Tsg increases chordin's binding of BMP4, potentiates chordin's ability to induce secondary axes in Xenopus embryos, and enhances chordin cleavage by vertebrate tolloid-related proteases at a site poorly used in Tsg's absence; also, the presence of Tsg enhances the secondary axis-inducing activity of two products of chordin cleavage. We conclude that Tsg acts as a cofactor in chordin's antagonism of 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 expression patterns in Xenopus and mouse embryos.
Figure 2: Tsg alters cleavage of chordin by BMP1 and mTll1, and directly interacts with chordin and BMP4 to enhance chordin/BMP4 complex formation.
Figure 3: Tsg potentiates secondary axis induction by chordin and chordin fragments and increases their binding of BMP4.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Data deposits

The GenBank accession numbers for full-length human, Xenopus, zebrafish and chick Tsg sequence are AF196834, AF279246, AF261692 and AF255731, respectively.

Change history

References

  1. 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 

  2. Francois, V., Solloway, M., O'Neill, J. W., Emery, J. & Bier, E. Dorsal-ventral patterning of the Drosophila embryo depends on a putative negative growth factor encoded by the short gastrulation gene. Genes Dev. 8, 2602– 2616 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Marqués, 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– 426 (1997).

    Article  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. Scott, I. C. et al. Mammalian BMP-1/ Tolloid-related metalloproteinases, including novel family member mammalian tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev. Biol. 213, 283– 300 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Sasai, Y. et al. Xenopus chordin: A novel dorsalizing factor activated by organizer-specific homeobox genes. Cell 79, 779– 790 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blitz, I. L., Shimmi, O., Wünnenberg-Stapleton, K., O'Connor, M. B. & Cho, K. W. Y. Is Chordin a long-range or short-range acting factor? Roles for BMP1-related metalloproteases in regulating chordin action. Dev. Biol. 223, 120– 138 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Larraín, J. et al. BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 127, 821– 830 (2000).

    PubMed  Google Scholar 

  12. Arora, K., Levine, M. S. & O'Connor, M. B. The screw gene encodes a ubiquitously expressed member of the TGF-β family required for specification of dorsal cell fates in the Drosophila embryo. Genes Dev. 8, 2588– 2601 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. Holley, S. A. et al. A conserved system for dorsal–ventral patterning in insects and vertebrates involving sog and chordin. Nature 376, 249– 253 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Zusman, S. B., Sweeton, D. & Wieschaus, E. F. Short gastrulation, a mutation causing delays in stage specific cell shape changes during gastrulation in Drosophila melanogaster. Dev. Biol. 129, 417– 427 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. Ross, J. J. et al. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410, 479– 483 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Kohfeldt, E., Maurer, P., Vannahme, C. & Timpl, R. Properties of the extracellular calcium binding module of the proteoglycan testican. FEBS Lett. 414, 557– 561 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Zhu, Y., Oganesian, A., Keene, D. R. & Sandell, L. J. Type IIA procollagen containing the cysteine-rich amino propeptide is deposited in the extracellular matrix of prechondrogenic tissue and binds to TGF-beta 1 and BMP-2. J. Cell Biol. 144, 1069– 1080 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pappano, W. N. et al. Coding sequence and expression patterns of mouse Chordin and mapping of the cognate mouse Chrd and human CHRD genes. Genomics 52, 236– 239 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, S., Solow-Cordero, D. E., Kessler, E., Takahara, K. & Greenspan, D. S. Transforming growth factor-β regulation of bone morphogenetic protein-1/procollagen C-proteinase and related proteins in fibrogenic cells and keratinocytes. J. Biol. Chem. 272, 19059– 19066 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. 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, 111– 1120 (1991).

    Article  Google Scholar 

  25. Harland, R. M. in Methods in Cell Biology (eds Kay, B. K. & Peng, H. B.) 685– 695 (Academic, San Diego, 1991).

    Google Scholar 

  26. Takahara, K., Lyons, G. E. & Greenspan, D. S. Bone morphogenetic protein-1 and a mammalian tolloid homologue (mTld) are encoded by alternatively spliced transcripts which are differentially expressed in some tissues. J. Biol. Chem. 269, 32572– 32578 (1994).

    CAS  PubMed  Google Scholar 

  27. Furuta, Y., Piston, D. W. & Hogan, B. L. M. Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 124, 2203– 2212 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. O'Connor for the mouse Tsg cDNA clone, J. Fallon for the chick embryo cDNA library, and B. Hogan for BMP2, -4, and -7 cDNA clones. We also thank E. De Robertis and C. Niehrs for Xenopus chordin and Vent2 cDNAs, respectively; S. Kinoshita for technical assistance; T. Koide for technical advice on embryo bleaching; and M. O'Connor, L. Marsh and A. Hemmati-Brivanlou for communicating their work before publication. This work was supported by the NIAMS (D.S.G), NIGMS (D.S.G. and K.W.Y.C.) and NICHD (K.W.Y.C.) of the National Institutes of Health, and by FibroGen (D.S.G.).

Author information

Author notes

  1. Ian C. Scott, Ira L. Blitz, William N. Pappano, Sarah A. Maas and Daniel S. Greenspan: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine,

    Ian C. Scott & Daniel S. Greenspan

  2. Department of Biomolecular Chemistry, University of Wisconsin Medical School, 1300 University Avenue, Madison, 53706, Wisconsin, USA

    William N. Pappano, Sarah A. Maas & Daniel S. Greenspan

  3. Department of Developmental and Cell Biology, and the Developmental Biology Center, University of California, Irvine, 92697, California, USA

    Ira L. Blitz & Ken W. Y. Cho

Authors
  1. Ian C. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ira L. Blitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William N. Pappano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah A. Maas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken W. Y. Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel S. Greenspan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel S. Greenspan.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scott, I., Blitz, I., Pappano, W. et al. Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling. Nature 410, 475–478 (2001). https://doi.org/10.1038/35068572

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35068572

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