(26g) Invited Speaker: Quantitative Models of Cell-Cell Signaling in Development

Proper signaling between cells in both animal development and adult homeostasis is crucial for the health of the organism, while misregulated signaling results in disease states. The goal of our lab is to understand the regulation of intercellular signaling at a fundamental level to help advance knowledge of human health. However, cell-cell signaling is complex, and is highly dynamic by its very nature. As a result, live, quantitative measurements, combined with mechanistic and predictive models are becoming increasingly important to continue on the forefront of research.

Accordingly, we study patterning networks in the early fruit fly embryo as a model system. This model system is extraordinarily tractable and amenable to live and fixed imaging, genetic manipulations, transgenesis, and formulation/analysis of mechanistic models. Here we will discuss the Dorsal/NF-κB signaling network, which patterns the embryo’s dorsal-ventral (DV) axis. Dorsal, a transcription factor, is retained in the cytoplasm through binding to the inhibitor, Cactus/IκB. Toll signaling on the ventral side of the embryo results in the degradation of Cactus (Cact) and the import of Dorsal into the nucleus. This results in a ventral-to-dorsal nuclear concentration profile (gradient) of Dorsal. The cells in the embryo respond to the Dorsal gradient in a concentration-dependent fashion. In this way, a single signal through Dorsal directs the differentiation of multiple domains of sub-tissue types.

Our recent quantitative measurements of the Dorsal concentration gradient, together with detailed modeling, have shown that the interplay between diffusion, nuclear transport, and binding with the inhibitor Cact results in a series of non-intuitive properties of the Dorsal concentration gradient. In particular, the inhibitor Cact serves to (1) increase the signaling strength on the ventral side of the embryo through a mechanism of facilitated diffusion, and to (2) reduce noise in Dorsal signaling by regulating Dorsal levels inside the nuclei.