Project 3. An interdisciplinary approach to studying epidermal growth factor receptor signaling dynamics in epithelial tissues (N. Yakoby, Biology; B. Piccoli, Mathematics)

Background. Epidermal growth factor receptor (EGFR) signaling in epithelial tissues is initiated by a source of a ligand activating transiently the pathway [1-7]. The regulation of signaling through ligand diffusion and distribution is still not understood.  An established model, Drosophila oogenesis, is an excellent system to study EGFR signaling regulating eggshell morphogenesis. The EGF-like ligand Gurken (GRK) is secreted from near the oocyte nucleus and activates EGFR in the overlaying follicle cells, which then form 3D eggshell structures (e.g. dorsal respiratory appendages, dorsal ridge) [8, 9]. The nucleus is a source of the ligand GRK, moving from posterior to anterior. GRK distribution, and consequently EGFR activation, is different among Drosophila species, corresponding to the formation of different morphologies [10]. Furthermore, GRK is necessary and sufficient to form a dorsal ridge [11].

Research. Using experimental and computational tools, students will study the mechanisms underlying   the evolution of EGFR signaling dynamics in epithelial tissues. Current computational models focus on D. melanogaster and use a fixed source of the ligand GRK [12]. We developed a model with a moving source of the ligand that recapitulates the distributions of EGFR signaling in the follicle cells. We propose to develop the model further into a 2D dynamic simulation of signaling. In addition, students will learn to determine the dynamics of EGFR signaling in species with different activation patterns. These mechanistic mathematical models will aid to study and predict the components of the pathway contributing to the differences in signaling dynamics among species. 

Student activities. Building on our previous successful experiences with REU programs [9, 10], students will lean both experimental and computational aspects of research. Experimentally, students will use antibodies against GRK to monitor ligand distribution, and antibodies against dpERK to monitor the corresponding activation pattern of EGFR, as was previously done for Drosophila species [10, 11, 13]. Students will learn to use a confocal microscope and document their findings. Based on these data, students will learn to use Matlab and program basic numerical methods for partial differential equations to simulate the signaling dynamics. Yakoby and Piccoli have been collaborating for a few years on a similar project; students will be guided on the experimental and computational aspects of the project.