Synergistic Antagonism

Abstract

The gene twisted gastrulation ( tsg ) was originally identified in Drosophila in screens for genes that disrupt gastrulation, resulting in the loss of the dorsal-most structure, the amnioserosa (see Harland for a description of this embryonic signaling pathway). Three papers describe the characterization of the Tsg protein in flies and vertebrates (Chang et al. , Scott et al. , and Ross et al. ). Chang et al. and Scott et al. demonstrate that Tsg is an antagonist of bone morphogenic protein (BMP) signaling and enhances the antagonist properties of another inhibitor of BMP4, chordin, in Xenopus embryos. Both groups also show, by coimmunoprecipiation experiments, that chordin, BMP4, and Tsg form a ternary complex and that Tsg promotes the chordin-BMP4 interaction. Scott et al. showed that Tsg regulated the cleavage products produced from mouse chordin by two Tolloid-like proteases, BMP1 and mTllI. Finally, Ross et al. examined the role of Tsg in the fly and zebrafish model organisms. Examination of tsg mutant phenotypes in the fly and zebrafish also support a role for Tsg as an inhibitor of BMP signaling, and when coexpressed with chordin in zebrafish, there was enhanced antagonism of BMP signaling than observed with either protein alone. Ross et al. demonstrate inhibition of signaling by the BMP ligand, decapentaplegic (DPP), when S2 cultured cells are treated with a mixture of the BMP antagonist SOG, Tsg, and DPP, compared with the signaling detected when DPP is added with only one of the antagonists, either SOG or Tsg. Thus, the interaction of these three proteins may contribute to the mechanism by which the BMP signaling gradients are established during development. R. M. Harland, A twist on embryonic signalling. Nature 410 , 423-424 (2001). [Online Journal] C. Chang, D. A. Holtzman, S. Chau, T. Chickering, E. A. Woolf, L. M. Holmgren, J. Bodorova, D. P. Gearing, W. E. Holmes, A. H. Brivanlou, Twisted gastrulation can function as a BMP antagonist. Nature 410 , 483-4872001). [Online Journal] I. C. Scott, I. L. Blitz, W. N. Pappano, S. A. Maas, K. W. Y. Cho, D. S. Greenspan, Homologues of twisted gastrulation are extracellular cofactors in antagonism of BMP signalling. Nature 410 , 475-478 (2001). [Online Journal] J. J. Ross, O. Shimmi, P. Vilmos, A. Petryk, H. Kim, K. Gaudenz, S. Hermanson, S. C. Ekker, M. B. O'Connor, J. L. Marsh, Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410 , 479-483 (2001). [Online Journal]