DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a highly-conserved regulator of tissue development across animals. Faulty regulation of signaling is associated with developmental defects and pathologies such as cancers. The complexity of the EGFR activation network has been extensively studied; however, the coordinating mechanisms of multiple EGFR components are only partially understood. Furthermore, the mechanisms governing signaling changes that guide the formation of new morphologies across tissues have been only sparsely studied. The ovaries of Drosophila melanogaster provide a tractable genetic system to study mechanisms governing spatiotemporal differences of EGFR activation in the follicle cells (FCs), a 2D layer of epithelial cells surrounding the developing oocyte. Instructed mainly by the germline secreted TGF-beta-like ligand Gurken (GRK), the FCs form the 3D morphologies of the eggshell. One morphology is a structure with a lumen, the dorsal ridge, along the dorsal side of eggshells of numerous species from major clades of the genus Drosophila. Strikingly, we found quantitative and qualitative associations among EGFR activation domains, GRK protein distributions, and varieties of dorsal ridge morphologies. Combining molecular, genetic, and mathematical modeling approaches, we aim to determine the mechanisms governing different activation levels of EGFR in epithelial tissues across different species. Our experimental and modeling preliminary results support ligand localization to the oocyte and FCs' membranes, and the perivitelline space to underlie different signaling distributions in the 2D FCs. Considering the conserved nature of EGFR activation across animals, we expect to discover new mechanisms that control the levels of EGFR activation, which may become targets of drug development to treat tissue pathologies.
|Effective start/end date||8/1/13 → 8/31/20|
- National Institutes of Health: $353,378.00
- National Institutes of Health: $452,829.00
- Biochemistry, Genetics and Molecular Biology(all)