Dominant Mutation that Affect EGF-R Signal Transduction

描述(改编自调查人员摘要)：这是一个长远的目标 建议了解表皮生长因子受体(EGF-R)是如何 在后生动物发育过程中受到控制。隐性功能丧失突变 受体酪氨酸激酶(RTK)信号转导的许多通用成分 SOS、RAS、RAF和MAPK等途径已在以前的 筛选剂量敏感的RTK信号抑制和增强因子 突变。虽然前面的筛查对识别基因突变很有用 许多RTK信号基因，它们可能遗漏了存在的成分 多余的或无限量的。另外，之前的屏幕一般 分离的信号基因功能丧失等位基因，而上位性 这些基因之间的关系主要是通过 显性突变的分离和鉴定。基因的显性突变 基因也被广泛地用来分析较少的 基因易驯化的脊椎动物组织培养系统。调查人员 提出了一种新的基因筛查，它将允许分离显性 相关基因的功能获得和显性功能丧失突变 EGF-R等信号转导通路。抑制或抑制的基因 激活EGFR信号将通过分离显性雌性不育来识别 (DFS)突变，破坏细胞的分化或增殖 卵室周围的滤泡细胞。基因筛查涉及 使用新开发的技术恢复镶嵌动物的突变。 初步的基因筛查已经确定了两个基因的DFS突变， 明星-科贾克和乌格拉-DFS。这两个DFS突变都产生了它们的表型 通过下调周围毛囊细胞中的EGF-R信号 卵母细胞。Star和Ugra的功能丧失等位基因的表型表明 他们可能参与了鲜为人知的配基生产领域 和展示。因为其他信号转导途径，如那些 涉及无翼、Notch、TGFb和Hedgehog，也涉及卵泡细胞 发展，所提出的筛查的另一个优点是毛囊细胞 影响这些其他途径的依赖DFS突变也可能是 与世隔绝。以达到了解EGF-R调控的目的。 三个目标是最重要的。首先，他们将进行额外的.基因 筛选分离其他基因中的显性突变，如Star-Kojak和Ugra-DFS 涉及EGF-R和其他信号转导途径的基因。第二， 将对UGRA进行分子分析，以了解它编码什么以及它编码什么 它在EGF-R信号转导中发挥作用。第三，他们将执行一项详细的 Star-Kojak和Star功能丧失的分子和表型分析 等位基因更好地了解Star在EGF-R信号转导中的作用。它 对于理解RTK信号的调节很重要，因为RAS-Raf 依赖性肿瘤占所有人类癌症的五分之一。

DESCRIPTION (adapted from investigator's abstract): The long-range goal of this proposal is to understand how the Epidermal Growth Factor Receptor (EGF-R) is controlled during metazoan development. Recessive loss-of-function mutations in many general components of receptor tyrosine kinase (RTK) signal transduction pathways, such as Sos, Ras, Raf, and MAPK, have been identified in previous screens for dosage-sensitive suppressors and enhancers of RTK signaling mutations. While the previous screens are useful in identifying mutations in many RTK signaling genes, they might have missed components that are present redundantly or in non-limiting amounts. Also, the previous screens generally isolated loss-of-function alleles of signaling genes, whereas the epistatic relationships among these genes has been determined primarily through the isolation and characterization of dominant mutations. Dominant mutations in genes have also been extensively used to analyze signaling pathways in the less genetically tractable vertebrate tissue culture systems. The investigators propose a novel genetic screen which will allow the isolation of dominant gain-of-function and dominant loss-of function mutations in genes involved in EGF-R and other signal transduction pathways. Genes that either inhibit or activate EGFR signaling will be identified by isolating dominant female sterile (DFS) mutations that disrupt the differentiation or proliferation of the follicle cells that surround the egg chambers. The genetic screen involves using newly developed techniques to recover mutations from mosaic animals. Preliminary genetic screens have already identified DFS mutations in two genes, Star-Kojak and Ugra-DFS. Both of these DFS mutations generate their phenotypes by down-regulating EGF-R signaling in the follicle cells that surround the oocyte. Loss-of-function alleles of Star and Ugra have phenotypes that suggest that they might be involved in the poorly understood area of ligand production and presentation. Since other signal transduction pathways' such as those that involve wingless, Notch, TGFb and hedgehog, are also involved in follicle cell development, a further advantage of the proposed screen is that follicle-cell dependent DFS mutations that affect these other pathways could also be isolated. In order to accomplish their goal of understanding EGF-R regulation. three objectives are paramount. Firstly, they will conduct additional .genetic screens to isolate dominant mutations, like Star-Kojak and Ugra-DFS, in other genes involved in EGF-R and other signal transduction pathways. Secondly, molecular analysis of Ugra will be performed to learn what it encodes and what role it plays in EGF-R signaling. Thirdly, they will perform a detailed molecular and phenotypic analysis of Star-Kojak and Star loss-of-function alleles to better understand the role of Star in EGF-R signal transduction. It is important to understand regulators of RTK signaling because Ras-Raf dependent neoplasia accounts for as many as one-fifth of all human cancers.