This research project investigates the mechanisms that activate the Drosophila Epidermal Growth Factor receptor (Egfr) during oogenesis, and the cellular pathways that mediate the response to this receptor tyrosine kinase in the ovarian follicle cells. Cell-cell communication plays an important role in the development of many tissues. Our model system focuses on signaling between the female germline and its surrounding follicle cells in the ovary of Drosophila melanogaster. We have shown that the Drosophila Egfr is expressed in the follicle cells and receives a highly controlled signal from the germline encoded by the gene gurken (grk). Restricted activation of the Egfr by Grk initiates several different follicle cell responses and is required for axis formation of the egg and embryo. We have also shown that grk expression in oogenesis can be regulated by a checkpoint mechanism. Problems in DNA repair during meiosis as well as other nuclear defects caused by retrotransposons, activate a meiotic checkpoint that controls translation of Grk in the oocyte cytoplasm. Our goal is to study the regulation of Gurken production in the germline and to analyze the patterning and differentiation processes that are activated in the follicle cells in response to receptor activation.
Our specific aims are: 1) Checkpoint mediated control of Gurken production: 1A) The role of cutoff (cuff) in the piRNAi pathway. We have found that the gene cuff is a component of the piRNAi pathway that guards the germline against retrotransposon damage. Mutations in cuff activate a germline checkpoint. We will determine the molecular role of cuff in the piRNAi pathway and its effect on checkpoint activation. 1B) Translational regulation of gurken RNA. We will determine how the meiotic checkpoint regulates translation of grk. This will involve analysis of the gene vasa, as well as the translation initiation factor eIF1A that affects Grk protein levels in the checkpoint activated germline. 3) Analysis of the response pathway acting in the follicle cells of the ovary. We have defined several specific patterning responses to Egfr activation in the follicle cells. In particular, we have isolated mutations that affect posterior follicle cell differentiation and uncover interactions of Egfr signaling with the Notch pathway. We will analyze mutations in two genes that will allow us to describe the complex interactions of the two pathways in the posterior follicle cells. We will also compare the response of posterior follicle cells to that of dorsal follicle cells. Mutations in checkpoint genes, as well as unregulated activation of the human homologs of Egfr have been implicated in several forms of cancer. Our work will elucidate new roles of checkpoint genes, as well as analyzing the normal cellular pathways that regulate the activity of this receptor. It will also define downstream effector pathways operating in the follicle cell epithelium, a model system for epithelial development and differentiation.

Public Health Relevance

This project investigates the regulation and the effects of the Drosophila Epidermal Growth Factor receptor. In humans, this type of receptor is frequently mutated in cancer, in particular in breast cancer, and novel drugs that target this receptor have already shown great promise in the fight against cancer. Our work identifies further genes that act in the same pathway as the receptor and these genes will provide new targets for specific cancer drugs as well as allowing us to address side effects of available cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077620-06
Application #
8233454
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2007-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$318,223
Indirect Cost
$118,223
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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Yan, Yan; Denef, Natalie; Tang, Charm et al. (2011) Drosophila PI4KIIIalpha is required in follicle cells for oocyte polarization and Hippo signaling. Development 138:1697-703
Sethi, Nilay; Yan, Yan; Quek, Debra et al. (2010) Rabconnectin-3 is a functional regulator of mammalian Notch signaling. J Biol Chem 285:34757-64

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