EGF receptor mediated signaling in Drosophila

果蝇中 EGF 受体介导的信号传导

• 批准号: 8415533
• 负责人: Gertrud M. Schupbach
• 金额: $ 30.71万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415533
• 关键词: Address; Adverse effects; Affect; Anterior; Antineoplastic Agents; Biological Models; Cell Communication; Cell Differentiation process; Cells; Complex; Cytoplasm; DNA Damage; DNA Repair; Defect; Development; Dorsal; Down-Regulation; Drosophila genus; Drosophila melanogaster; Drug Targeting; Egg Shell; Embryo; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Female; Funding; Gene Targeting; Genes; Germ Cells; Goals; Homologous Gene; Human; Link; Malignant Neoplasms; Mediating; Meiosis; Modeling; Modification; Molecular; Mutate; Mutation; Nature; Nuclear; Oocytes; Oogenesis; Organism; Ovarian Follicle; Ovary; Pathway interactions; Pattern; Peptide Initiation Factors; Phosphotransferases; Play; Process; Production; Proteins; RNA; Receptor Activation; Receptor Gene; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Repression; Research; Research Project Grants; Retrotransposon; Role; Signal Pathway; Signal Transduction; Stem cells; Tissues; Translational Regulation; Translations; Work; computerized data processing; egg; fight against; insight; malignant breast neoplasm; notch protein; novel; public health relevance; receptor; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：这项研究项目调查了在卵子发生过程中激活果蝇表皮生长因子受体(EGFR)的机制，以及在卵巢卵泡细胞中介导对该受体酪氨酸激酶反应的细胞途径。细胞间的通讯在许多组织的发育中起着重要的作用。我们的模型系统专注于果蝇卵巢中雌性生殖系与其周围的卵泡细胞之间的信号传递。我们已经证明，果蝇EGFR在毛囊细胞中表达，并从由Gurken(Grk)基因编码的生殖系接收高度受控的信号。GRK对EGFR的限制性激活启动了几种不同的滤泡细胞反应，这是卵和胚胎轴形成所必需的。我们还表明，在卵子发生过程中，Grk的表达可以通过检查点机制进行调节。在减数分裂过程中的DNA修复问题以及由反转录转座子引起的其他核缺陷，激活了一个减数分裂检查点，该检查点控制着Grk在卵母细胞细胞质中的翻译。我们的目标是研究生殖系中Gurken产生的调节，并分析卵泡细胞中响应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)检查点介导的gurken生产控制：1)切断(Cuff)在piRNAi途径中的作用。我们已经发现，基因袖带是piRNAi途径的一个组成部分，它保护生殖系免受反转录转座子的破坏。袖带中的突变激活了生殖系检查点。我们将确定Cuff在piRNAi途径中的分子作用及其对检查点激活的影响。1b)Gurken RNA的翻译调控。我们将确定减数分裂检查点如何调控grk的翻译。这将涉及分析VasA基因，以及影响检查点激活生殖系中Grk蛋白水平的翻译起始因子eIF1a。3)卵巢卵泡细胞的反应途径分析。我们已经在毛囊细胞中定义了几种对EGFR激活的特定图案化反应。特别是，我们分离出了影响后部毛囊细胞分化的突变，并发现了EGFR信号与Notch通路的相互作用。我们将分析两个基因的突变，这将使我们能够描述这两个通路在后毛囊细胞中的复杂相互作用。我们还将比较后部毛囊细胞和背部毛囊细胞的反应。检查点基因的突变，以及人类EGFR同源物的无调控激活，都与几种形式的癌症有关。我们的工作将阐明检查点基因的新作用，以及分析调节该受体活性的正常细胞途径。它还将定义在毛囊细胞上皮中运行的下游效应通路，毛囊细胞上皮是上皮发育和分化的模型系统。