Dissecting input-output relationships of Developmental BMP Signaling

ABSTRACT
A small number of conserved signaling pathways are key players in cell fate decisions that govern embryonic
development, maintenance and health of adult tissues, and progression of disease states. For example,
embryonic development in numerous species hinges on the dynamics and regulation of the BMP signaling
pathway. 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.
This study aims to shed light on how cells perceive and respond to varying BMP signaling inputs, with the goal
that these discoveries will be broadly applicable to other biological contexts. The proposed research program
employs cutting-edge quantitative live imaging techniques, the creation of predictive mathematical models, and
the adaptation of tools for studying BMP signaling in diverse insect species. Specifically, I will develop a
predictive model for BMP target gene transcription that can correlate BMP signaling dynamics with timing and
spatial patterns of gene expression. Second, I will examine crosstalk between BMP signaling and EGFR/ERK
signaling by developing live imaging approaches and applying quantitative methods. Finally, I will expand the
research scope by building tools to examine BMP signaling dynamics in the red flour beetle, Tribolium
casteneum. By leveraging the unique characteristics of Tribolium, such as slower development and distinct
embryonic tissue architecture, I will elucidate how the conserved BMP signaling pathway adapts and functions
across species. The proposed multi-faceted approach, ranging from mathematical modeling to cross-species
comparisons, promises to unveil fundamental principles of cell signaling and provide a foundation for further
advancements in developmental biology and translational applications. To accomplish these goals, I have
formed an exceptional committee of advisors who can aid in my diverse approach to understanding signaling
dynamics in vivo. Together with my advisor, Dr. Stefano Di Talia, I have designed a training plan that will provide
me with the skills required to run a productive, independent laboratory that tackles complex questions about
the role of conserved signaling in developmental biology.

Grant Number: 5K99HD115781-02
NIH Institute/Center: NIH
Principal Investigator: Susanna Brantley