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Twisted gastrulation can function as a BMP antagonist

Nature volume 410, pages 483–487 (2001)Cite this article

Abstract

Bone morphogenetic proteins (BMPs), including the fly homologue Decapentaplegic (DPP), are important regulators of early vertebrate and invertebrate dorsal–ventral development1,2,3,4,5,6. An evolutionarily conserved BMP regulatory mechanism operates from fly to fish, frog and mouse to control the dorsal–ventral axis determination. Several secreted factors, including the BMP antagonist chordin/Short gastrulation (SOG)7,8,9,10,11,12, modulate the activity of BMPs. In Drosophila, Twisted gastrulation (TSG) is also involved in dorsal–ventral patterning13,14,15, yet the mechanism of its function is unclear. Here we report the characterization of the vertebrate Tsg homologues. We show that Tsg can block BMP function in Xenopus embryonic explants and inhibits several ventral markers in whole-frog embryos. Tsg binds directly to BMPs and forms a ternary complex with chordin and BMPs. Coexpression of Tsg with chordin leads to a more efficient inhibition of the BMP activity in ectodermal explants. Unlike other known BMP antagonists, however, Tsg also reduces several anterior markers at late developmental stages. Our data suggest that Tsg can function as a BMP inhibitor in Xenopus; furthermore, Tsg may have additional functions during frog embryogenesis.

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Figure 1: Vertebrate Tsgs inhibit BMP signalling in embryonic explants.
Figure 2: Overexpression of Tsg perturbs early Xenopus development and interferes with formation of tissues that require active BMP signalling.
Figure 3: Membrane-tethered Xenopus Tsg induces partial secondary axis when expressed in the ventral region.
Figure 4: Xenopus Tsg binds to Bmp4, forms a ternary complex with chordin and Bmp4, and coexpression of chordin and Tsg leads to a more efficient inhibition of BMP activity in ectodermal explants.

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Acknowledgements

We thank K. Lee and T. Jessell for providing the chick chordin construct; G. Struhl for providing the CD2 construct; A. Economides for technical advice on biochemical studies; and P. Wilson, D. Weinstein, E. Bell and I. Zohn for critical reading of the manuscript. We are grateful to M. O'Connor, K. Cho, L. Marsh and D. Greenspan for communicating their results before publication. This work is supported by an NIH grant to A.H.B., who is a McKnight, Merck and Klingenstein scholar.

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Author notes

  1. Douglas A. Holtzman

    Present address: Microbia, Inc., One Kendall Square, Building 1400W Suite, 1418, Cambridge, Massachusetts, 02139, USA

  2. Jana Bodorova

    Present address: SAIC/NCI-FCRDC, Building 560/21–50, Frederick, Maryland, 21702, USA

  3. David P. Gearing

    Present address: CSL Limited, 45 Poplar Road, Parkville, Vic, 3052, Australia

Authors and Affiliations

  1. Laboratory of Vertebrate Molecular Embryology, The Rockefeller University, Box 32, 1230 York Avenue, New York, 10021, New York, USA

    Chenbei Chang & Ali H. Brivanlou

  2. Millennium Pharmaceuticals, 620 Memorial Drive, Cambridge, 02139, Massachusetts, USA

    Douglas A. Holtzman, Samantha Chau, Troy Chickering, Elizabeth A. Woolf, Lisa M. Holmgren, Jana Bodorova, David P. Gearing & William E. Holmes

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Correspondence to Ali H. Brivanlou.

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Chang, C., Holtzman, D., Chau, S. et al. Twisted gastrulation can function as a BMP antagonist. Nature 410, 483–487 (2001). https://doi.org/10.1038/35068583

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