Abstract
The BMP signaling pathway has a conserved role in dorsal-ventral axis patterning during embryonic development. In Drosophila, graded BMP signaling is transduced by the Mad transcription factor and opposed by the Brinker repressor. In this study, using the Drosophila embryo as a model, we combine RNA-seq with Mad and Brinker ChIP-seq to decipher the BMP-responsive transcriptional network underpinning differentiation of the dorsal ectoderm during dorsal-ventral axis patterning. We identify multiple new BMP target genes, including positive and negative regulators of EGF signaling. Manipulation of EGF signaling levels by loss- and gain-of-function studies reveals that EGF signaling negatively regulates embryonic BMP-responsive transcription. Therefore, the BMP gene network has a self-regulating property in that it establishes a balance between its activity and that of the antagonistic EGF signaling pathway to facilitate correct patterning. In terms of BMP-dependent transcription, we identify key roles for the Zelda and Zerknüllt transcription factors in establishing the resulting expression domain, and find widespread binding of insulator proteins to the Mad and Brinker-bound genomic regions. Analysis of embryos lacking the BEAF-32 insulator protein shows reduced transcription of a peak BMP target gene and a reduction in the number of amnioserosa cells, the fate specified by peak BMP signaling. We incorporate our findings into a model for Mad-dependent activation, and discuss its relevance to BMP signal interpretation in vertebrates.
Highlights
The Bone Morphogenetic Protein (BMP) signaling pathway is used repeatedly throughout development to regulate a diverse array of processes
We have used genomics approaches to identify the gene expression programme implemented in response to BMP signaling
Dpp-Scw signaling through a Thickveins (Tkv), Punt and Saxophone receptor complex results in phosphorylation of the C-terminal tail of the Mothers Against Dpp (Mad) transcription factor, which interacts with Medea (Med), leading to their stabilization in the nucleus [2]
Summary
The Bone Morphogenetic Protein (BMP) signaling pathway is used repeatedly throughout development to regulate a diverse array of processes. One of the major conserved roles of the BMP pathway is to specify epidermal fates during embryonic dorsal-ventral axis patterning [1]. In Drosophila, a heterodimer of the BMP signaling molecules, Decapentaplegic (Dpp) and Screw (Scw), forms a gradient in order to pattern the dorsal ectoderm of the embryo into dorsal epidermis and amnioserosa fates. Dpp-Scw signaling through a Thickveins (Tkv), Punt and Saxophone receptor complex results in phosphorylation of the C-terminal tail of the Mothers Against Dpp (Mad) transcription factor (pMad), which interacts with Medea (Med), leading to their stabilization in the nucleus [2]. Nuclear pMad is observed around the dorsal midline following extracellular transport of the Dpp-Scw ligand as the first step in gradient formation [2]. Studies in flies and vertebrates have revealed complex regulation of Smad transcription factors by phosphorylation, dephosphorylation, SUMOylation and ubiquitination, which controls their subcellular localization, transcriptional activity and degradation [1, 4]
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