title: The pro-BMP activity of Twisted gastrulation is independent of BMP binding.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Biological Chemistry, University of California-Los Angeles, Los Angeles, CA 90095-1662, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oelgeschläger
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.forename: Juan
authors.initials: J
authors.lastname: Larraín
authors.forename: Shawn
authors.initials: S
authors.lastname: Little
authors.forename: Mary C
authors.initials: MC
authors.lastname: Mullins
authors.forename: E M
authors.initials: EM
authors.lastname: De Robertis
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C477670:TWSG1 protein, Xenopus; D029867:Xenopus Proteins; D028341:Activins; C054234:chordin