Twisted gastrulation can function as a BMP antagonist

Abstract

Bone morphogenetic proteins (BMPs), including the fly homologue Decapentaplegic (DPP), are important regulators of early vertebrate and invertebrate dorsal-ventral development. 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), modulate the activity of BMPs. In Drosophila, Twisted gastrulation (TSG) is also involved in dorsal-ventral patterning, 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.

Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR

“…Specifically, BMP4 levels were repressed by both Pax3 and Pax3/FKHR. Further, the BMP4 agonist, BMP1 (Wardle et al, 1999a, b), was also repressed, while an antagonist of BMP4, twisted gastrulation (TWGS; Yu et al, 2000;Chang et al, 2001;Ross et al, 2001;Scott et al, 2001), was induced in these cells. Since BMP4 signalling was repressed, we predicted and determined that one potential target of BMP4 signalling, Dlx3 (Luo et al, 2001;Park and Morasso, 2002), was also repressed following Pax3 and Pax3/ FKHR expression.…”

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

“…TSG orthologues have now been identified in various species, and in which they bind BMP4/DPP and Chordin/SOG in a ternary complex, and appear capable of either promoting or antagonizing BMP signaling in different in vivo contexts (Oelgeschlager et al, 2000;Chang et al, 2001;Ross et al, 2001;Scott et al, 2001). Although TSG does not appear to bind BMP1/ TLD-like proteinases, it does enhance the Chordinase activity of BMP1 and mTLL1 ).…”

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

“…For example, BMP1 and its Drosophila counterpart, Tolloid, unlike the other BMPs, are proteases that both function to cleave and thereby inactivate the BMP/Dpp antagonists chordin/sog (Marques et al, 1997;Blader et al, 1997;Goodman et al, 1998;Wardle et al, 1999). Twisted gastrulation is a direct-binding BMP antagonist/modulator that is also conserved between flies and vertebrates Chang et al, 2001;Ross et al, 2001;Scott et al, 2001). Thus, the dorsoventral antagonism of early Drosophila and Xe-nopus embryos is a sophisticated balancing of forces.…”