EGF receptor mediated signaling in Drosophila

描述（申请人提供）：细胞-细胞通讯在许多组织的发育中起着重要作用。本研究旨在探讨果蝇表皮生长因子受体（Egfr）在卵子发生过程中的激活机制，以及卵泡细胞对该受体酪氨酸激酶反应的细胞通路。我们已经证明果蝇Egfr在卵泡细胞中表达，并接受由基因gurken （grk）编码的来自种系的高度受控信号。受Grk限制的Egfr激活启动了几种不同的卵泡细胞反应，这是卵子和胚胎轴形成所必需的。我们还表明，grk在卵子发生中的表达受到发育输入和减数分裂检查点的调节。我们的目标是研究Grk在种系中产生的分子调控，并分析在受体激活的情况下，卵泡细胞中激活的模式和分化过程。我们的具体

DESCRIPTION (provided by applicant): Cell-cell communication plays an important role in the development of many tissues. 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. 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 formaton of the egg and embryo. We have also shown that grk expression in oogenesis is regulated by developmental inputs as well as a meiotic checkpoint. Our goal is to study the molecular regulation of Grk 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) The regulation of grk translation: We will identify proteins that bind to the grk RNA and regulate its translation using CRISPR technology. We will determine how the meiotic checkpoint regulates translation of grk and focus on the interaction of Vasa protein with the translation initiation factor eIF1A in the checkpoint activated germline. We will perform ribosome footprinting assays on the grk RNA which will allow us to determine the direct effects on ribosome binding by the developmental regulatory factors and by the meiotic checkpoint. 2) Analysis of the follicle cell response to EGFR activation. We will analyze the cooperation of the Egfr pathway with the Notch and JAK/STAT pathway during posterior follicle cell differentiation. We have isolated mutations that uncover interactions of Egfr signaling with the Notch pathway and will investigate these interactions at a molecular level. One focus is the transcriptional regulator Hamlet that acts downstream of Notch in neuronal cells. Transcriptional profiling and ChIP-Seq experiments will provide a global analysis of the cooperation between the signaling pathways. We will also analyze the cell biological response to Egfr signaling in the posterior follicle cells with a focus on the production of the posterior polarizing signal and its dependence on the actin cytoskeleton and microvilli. Mutations in checkpoint genes, as well as unregulated activation of the human Egfr have been implicated in several forms of cancer. Our work will elucidate the regulatory mechanisms that control the activity of this receptor in an in vivo situation. It will also analyze the interactions between Egfr and other signaling pathways and provide a molecular understanding of the downstream effector pathways operating in the follicle cell epithelium, a model system for epithelial development and differentiation.