Quantitative analysis of signaling dynamics across the BMP morphogen gradient

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ABSTRACT Our current knowledge of BMP signaling pathway specificity is based upon foundational genetic and in vitro experiments, but we have limited understanding as to how cells produce diverse but specific responses to similar signaling inputs in vivo. In the Drosophila embryo, a steep gradient of BMP signaling is dynamically established prior to gastrulation. This gradient is interpreted by different populations of cells to establish the dorsal-ventral axis of the embryo, with cells at the dorsal midline turning on a unique set of transcripts compared to more lateral cells. We do not know how the dynamics of gradient formation and the final gradient pattern are interpreted by cohorts of cells in the embryo to produce the correct spatiotemporal transcriptional response. Using new imaging tools and a quantitative systems level approach, I will be able to interrogate how upstream inputs to the BMP signaling pathway are decoded in the nucleus to elicit correct spatiotemporal transcriptional responses. In this study I will explore two potential mechanisms by which BMP signaling is encoded. First, new methods will allow me to assay the signaling dynamics of pathway activity along the BMP gradient. With these data I will build an input-output relationship model to predict the mechanisms that drive BMP-responsive transcriptional dynamics. Second, I will determine if different combinations of ligand and receptor pairs play a role in specification and interpretation of the BMP gradient. I will study how both dynamic and combinatorial signaling are used to produce the wild type pattern of BMP signaling responses in the embryo. Then, using genetic perturbations in key pathway components that propagate and shape the morphogen gradient, I will test if these input-output relationships in dynamics and combinatorial signaling hold true across different BMP signaling contexts. Successful completion of this study will provide a quantitative view for how a conserved signaling pathway is interpreted by cells in vivo across time and space.