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First published online July 21, 2003
doi: 10.1242/10.1242/dev.00633
1 Howard Hughes Medical Institute and Department of Biological Chemistry,
University of California, Los Angeles, CA 90095-1662, USA
2 University of Pennsylvania, Department of Cell and Developmental Biology, 421
Curie Boulevard, Philadelphia, PA 19104-6058, USA
Author for correspondence (e-mail:
derobert{at}hhmi.ucla.edu)
Accepted 20 May 2003
The determination of the vertebrate dorsoventral body axis is regulated in the extracellular space by a system of interacting secreted molecules consisting of BMP, Chordin, Tolloid and Twisted Gastrulation (Tsg). Tsg is a BMP-binding protein that forms ternary complexes with BMP and Chordin. We investigated the function of Tsg in embryonic patterning by generating point mutations in its two conserved cysteine-rich domains. Surprisingly, Tsg proteins with mutations in the N-terminal domain were unable to bind BMP, yet ventralized the embryo very effectively, indicating strong pro-BMP activity. This hyperventralizing Tsg activity required an intact C-terminal domain and could block the anti-BMP activity of isolated BMP-binding modules of Chordin (CRs) in embryonic assays. This activity was specific for CR-containing proteins as it did not affect the dorsalizing effects of Noggin or dominant-negative BMP receptor. The ventralizing effects of the xTsg mutants were stronger than the effect of Chordin loss-of-function in Xenopus or zebrafish. The results suggest that xTsg interacts with additional CR-containing proteins that regulate dorsoventral development in embryos.
Key words: Twisted-gastrulation, BMP, Chordin, Tolloid, Crossveinless, TGFß, Cell-cell signaling, Xenopus, Zebrafish, CR modules
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