EGF receptor mediated signaling in Drosphilia

描述（由申请人提供）：细胞间通讯在许多组织的发育中起重要作用。我们正在研究果蝇卵巢中雌性生殖细胞与其周围卵泡细胞之间的信号传导过程。我们已经表明，果蝇的表皮生长因子受体（Egfr）的同源物在卵泡细胞中表达，并从gurken基因编码的种系中接收高度受控的信号。Gurken（一种TGF-α样蛋白）对Egfr的限制性激活启动了几种不同的卵泡细胞反应，并且是卵子和胚胎轴形成所需的。我们的目标是研究生殖细胞中信号产生的调节以及卵泡细胞中响应于受体激活而激活的图案化和分化过程。我们的具体目标是：1）分析调节Gurken翻译的减数分裂检查点机制。我们已经表明，DNA修复在减数分裂过程中耦合通过减数分裂检查点的翻译控制在卵母细胞的细胞质中的Gurken。我们将使用遗传学和生物化学方法分析在这一途径中起作用的基因。2)Gurken RNA的翻译调控。我们将确定减数分裂检查点如何调节Gurken的翻译，并研究对Gurken起作用的翻译控制的其他机制。这将涉及对基因Vasa以及我们发现的影响Gurken蛋白水平的三个新基因的分析。3)作用于卵巢卵泡细胞的反应通路分析。我们已经定义了几个特定的模式化反应，在卵泡细胞中的Egfr激活。此外，Egfr也是卵泡细胞存活和正常细胞分化所必需的。我们将鉴定和分析在这些过程中起作用的下游靶基因。这将涉及分析在镶嵌卵泡细胞筛选中鉴定的新突变。检查点基因的突变以及Egfr的人类同源物的不受调节的激活与几种形式的癌症有关，特别是乳腺癌。我们的工作将阐明检查点基因的新作用，并分析调节这种受体活性的正常细胞途径。它还将定义在滤泡细胞上皮中操作的下游效应器通路，其作为上皮发育和分化的模型系统。

DESCRIPTION (provided by applicant): 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.