Cell-cell communication plays an important role in the development of many tissues. We are studying signaling processes between the female germline and its surrounding follicle cells in the ovary of Drosophila melanogaster. We have shown that the Drosophila homolog of the Epidermal Growth Factor Receptor (Egfr) is expressed in the follicle cells and receives a highly controlled signal from the germline encoded by the gene gurken. Restricted activation of the Egfr by Gurken (a TGF-alpha like protein) initiates several different follicle cell responses and is required for axis formation of the egg and embryo. Our goal is to study the regulation of signal production in the germline and the patterning and differentiation processes that are activated in the follicle cells in response to receptor activation.
Our specific aims are: 1) Analysis of a meiotic checkpoint mechanism that regulates Gurken translation. We have shown that DMA repair during meiosis is coupled via a meiotic checkpoint to translational control of Gurken in the oocyte cytoplasm. We will analyze genes that act in this pathway using both genetic and biochemical approaches. 2) Translational regulation of Gurken RNA. We will determine how the meiotic checkpoint regulates translation of Gurken as well as investigating other mechanisms of translational control that operate on Gurken. This will involve analysis of the gene Vasa as well as three new genes that we have found to affect Gurken protein levels. 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 addition, the Egfr is also required for survival and normal cellular differentiation of the follicle cells. We will identify and analyze target genes acting downstream in these processes. This will involve the analysis of new mutations identified in mosaic follicle cell screens. Mutations in checkpoint genes, as well as unregulated activation of the human homologs of Egfr have been implicated in several forms of cancer, notably breast 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, which serves as a model system for epithelial development and differentiation. ? ? ?
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