An evolutionarily conserved system that regulates dorsal-ventral patterning via the BMP, Chordin, Tolloid and Twisted gastrulation proteins

*Address correspondence to: Eddy M. De Robertis. Howard Hughes Medical Institute & Dept. of Biological Chemistry, University of California, Los Angeles, CA, USA. e-mail: derobert@hhmi.ucla.edu Dorsal-ventral patterning in vertebrate and Drosophila embryos is controlled by a system of interacting secreting proteins that include BMP, Chordin, Xolloid, Tolloid and Twisted gastrulation. Chordin, the molecule that generates the pattern, is a BMP antagonist that contains four cysteine rich (CR) domains that bind to BMP, blocking its binding to the receptor. Tolloid/Xolloid encodes a metalloproteinase that cleaves Chordin at two sites, restoring the ability of BMP to signal. Twisted gastrulation has two distinct and sequential activities in BMP signaling. First, Tsg makes Chordin a better BMP antagonist by forming a ternary complex that prevents binding of BMP to its cognate receptor. Second, after cleavage of Chordin by Xolloid, Tsg competes the residual activity of Chordin fragments and facilitates their degradation. This molecular pathway, in which Xolloid switches the activity of Tsg from a BMP antagonist to a pro-BMP signal once all endogenous full-length Chordin is degraded, helps explain how sharp borders between embryonic territories are generated during development.