Morphogen signaling feedback and dynamics in embryonic patterning

PROJECT SUMMARY Embryos often send instructions to their cells using diffusible signaling molecules called morphogens. In the classical model, the morphogen diffuses from a localized source to create a concentration gradient. Cells then ‘read’ this gradient by activating fate-determining genes in a concentration-dependent manner. However, recent observations have complicated this simple model for several well-studied morphogen patterning systems. First, embryos often employ extensive feedback on signaling, suggesting that developmental patterning requires more precise control than diffusion alone can offer. Second, cells can respond to signaling dynamics—rather than morphogen concentration alone—when making decisions. In this proposal, I will investigate how signaling feedback and dynamics influence developmental patterning by Nodal, a model morphogen that induces mesendoderm in vertebrate embryos. Nodal signaling is regulated by broadly conserved positive and negative feedback loops, however the purpose of this feedback remains a matter of debate. In Aim 1, I will test how positive feedback contributes to Nodal-mediated patterning by characterizing mesendodermal development in new zebrafish mutants that lack this regulatory feature. In Aim 2, I will leverage a new optogenetic pipeline for spatiotemporal control of Nodal signaling to test whether Nodal gradient dynamics influence germ layer selection. This proposal will clarify the mechanistic basis of Nodal gradient formation and interpretation in vertebrate development. The work completed in this proposal may clarify how Nodal misregulation creates birth defects in human embryos and may lay the groundwork for new tissue engineering methods that leverage signaling dynamics to control cell fate selection. From a training perspective, this proposal will greatly increase my quantitative biology skills and prepare me for a career as an independent investigator focusing on developmental biology.