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The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling

Abstract

Dorsal–ventral patterning in vertebrate and Drosophila embryos requires a conserved system of extracellular proteins to generate a positional information gradient. The components involved include bone morphogenetic proteins (BMP/Dpp), a BMP antagonist (Chordin/Short gastrulation; Chd/Sog) and a secreted metalloproteinase (Xolloid/Tolloid) that cleaves Chd/Sog. Here we describe Xenopus Twisted gastrulation (xTsg), another member of this signalling pathway. xTsg is expressed ventrally as part of the BMP-4 synexpression group and encodes a secreted BMP-binding protein that is a BMP signalling agonist. The data suggest a molecular mechanism by which xTsg dislodges latent BMPs bound to Chordin BMP-binding fragments generated by Xolloid cleavage, providing a permissive signal that allows high BMP signalling in the embryo. Drosophila Tsg also binds BMPs and is expressed dorsally, supporting the proposal that the dorsal–ventral axis was inverted in the course of animal evolution.

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Figure 1: Tsg shares two conserved regions with dTsg and is co-expressed with BMP-4 and BAMBI.
Figure 2: Microinjection of xTsg mRNA leads to ventralization of the embryo.
Figure 3: Tsg blocks secondary axis formation by CR1 downstream of Chordin cleavage by Xolloid.
Figure 4: Tsg binds to BMP specifically and directly.
Figure 5: The Tsg N-terminal domain is sufficient to interact with BMP-4, but not with Chordin.
Figure 6: Tsg competes for binding of BMP-4 with CR1 but not with full-length Chordin.
Figure 7: Loss of function of endogenous xTsg potentiates the activity of CR1 mRNA.

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Acknowledgements

We thank J. Fessler, L. Zipursky and members of our laboratory for comments on the manuscript, and U. Tran and A. Cuellar for technical assistance. M.O. and J.L. are HFSPO and Pew postdoctoral fellows, respectively. This work was supported by the NIH and the Howard Hughes Medical Institute.

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Correspondence to Eddy M. De Robertis.

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Oelgeschläger, M., Larraín, J., Geissert, D. et al. The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405, 757–763 (2000). https://doi.org/10.1038/35015500

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