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.

Public Health Relevance

The epidermal growth factor receptor (EGFR) signaling pathway is a major regulator of tissue development, and aberrant signaling is associated with developmental diseases and multiple types of cancers. Using genetics, molecular, and mathematical modeling tools in an established model system, Drosophila oogenesis, we will tackle fundamental questions in ligand distribution and epithelial tissue development that differentiate into functional organs. Considering the conserved nature of EGFR signaling across animals, mechanisms of signal coordination between the germline and soma found in Drosophila may identify new targets for drug development to cure tissue pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM101597-01A1
Application #
8497018
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2013-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$353,378
Indirect Cost
$125,392
Name
Rutgers University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
625216556
City
Camden
State
NJ
Country
United States
Zip Code
08102
Niepielko, Matthew G; Marmion, Robert A; Kim, Kenneth et al. (2014) Chorion patterning: a window into gene regulation and Drosophila species' relatedness. Mol Biol Evol 31:154-64