tsg and tld are also expressed in the dorsal ectoderm, while sog is expressed ventro-laterally in the neuroectoderm ( Francois et al., 1994 MarquГ©s et al., 1997 Mason et al., 1994). The most potent BMP signalling molecule in the early Drosophila embryo is a heterodimer of the BMP ligands Decapentaplegic (Dpp) and Screw (Scw) ( Shimmi et al., 2005b), which have uniform expression in the dorsal ectoderm ( St Johnston and Gelbart, 1987 Arora et al., 1994 Shimmi et al., 2005b). BMP gradient formation is mediated by a conserved network of regulators, including two BMP binding proteins, Sog/Chordin and Twisted Gastrulation (Tsg), as well as a protease, Tolloid (Tld) ( Madamanchi et al., 2021 Matsuda et al., 2016 Shilo et al., 2013). A key developmental role for BMPs is the patterning of the dorsal-ventral (DV) axis in early vertebrate and invertebrate embryos. BMPs bind to their receptors resulting in the phosphorylation of a receptor regulated Smad, which then forms a complex with the common mediator Smad that accumulates in the nucleus to regulate target gene transcription ( Schmierer and Hill, 2007). BMPs perform essential roles during animal development and adult tissue homeostasis, the significance of which is reflected in the variety of human diseases attributed to aberrant BMP activity ( Bandyopadhyay et al., 2013 Wang et al., 2014). This article has an associated First Person interview with the first author of the paper.Д«one morphogenetic proteins (BMPs) are a large class of highly conserved signalling molecules that belong to the TGF-beta superfamily. We discuss how this altered compactness may contribute to mechanistic differences in Sog and Chordin function during BMP gradient formation. The model suggests a more compact shape than the vertebrate ortholog Chordin and conformational flexibility between the C-terminal von Willebrand C domains. Additionally, we use experimental negative stain EM imaging and hydrodynamic data to validate the AlphaFold structure prediction for Sog. However, we show that the sog C27,28S mutant is viable with only very mild phenotypes, indicating that these residues and their potential modification are not critical for Sog secretion in vivo. As proof-of-principle, we test the requirement for two cysteine residues that were previously identified as targets for palmitoylation, which has been proposed to enhance Sog secretion. We generate a sog knockout fly stock, which allows simple reintegration of altered versions of the sog coding sequence. In this study, we combine genome editing, structural and developmental approaches to study Sog function in Drosophila. The extracellular BMP binding protein Short Gastrulation (Sog) in Drosophila plays a key role in BMP gradient formation. A BMP gradient is essential for patterning the dorsal-ventral axis of invertebrate and vertebrate embryos.

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