Processing of the Drosophila Sog protein creates a novel BMP inhibitory activity

Structurally unrelated neural inducers in vertebrate and invertebrate embry os have been proposed to function by binding to BMP4 or Dpp, respectively, and preventing these homologous signals from activating their receptor(s), In this study, we investigate the functions of various forms of the Drosoph ila Sog protein using the discriminating assay of Drosophila wing developme nt. We find that misexpression of Drosophila Sog, or its vertebrate counter part Chordin, generates a very limited vein-loss phenotype, This sog misexp ression phenotype is very similar to that of viable mutants of glass-bottom boat (gbb), which encodes a BMP family member. Consistent with Sog selecti vely interfering with Gbb signaling, Sog can block the effect of misexpress ing Gbb, but not Dpp in the wing. In contrast to the limited BMP inhibitory activity of Sog, we have identified carboxy-truncated forms of Sog, referr ed to as Supersog, which when misexpressed cause a broad range of dpp(-) mu tant phenotypes, In line with its phenotypic effects, Supersog can block th e effects of both misexpressing Dpp and Gbb in the wing. Vertebrate Noggin, on the other hand, acts as a general inhibitor of Dpp signaling, which can interfere with the effect of overexpressing Dpp, but not Gbb, We present e vidence that Sog processing occurs in vivo and is biologically relevant. Ov erexpression of intact Sog in embryos and adult wing primordia leads to the developmentally regulated processing of Sog, This in vivo processing of So g can be duplicated in vitro by treating Sog with a combination of the meta lloprotease Tolloid (Tld) plus Twisted Gastrulation (Tsg), another extracel lular factor involved in Dpp signaling. In accord with this result, coexpre ssion of intact Sog and Tsg in developing wings generates a phenotype very similar to that of Supersog, Finally, we provide evidence that tsg function s in the embryo to generate a Supersog-like activity, since Supersog can pa rtially rescue tsg(-) mutants. Consistent with this finding, sog(-) and tsg (-) mutants exhibit similar dorsal patterning defects during early gastrula tion, These results indicate that differential processing of Sog generates a novel BMP inhibitory activity during development and, more generally, tha t BMP antagonists play distinct roles in regulating the quality as well as the magnitude of BMP signaling.