GENETIC CONTROL OF EYE SPECIFICATION

描述(逐字摘自申请者摘要)：长期目标 这项建议是为了更好地了解人类的基因控制 果蝇眼组织的测定。几个发挥重要作用的基因 在这一过程中已经在最近几年被发现。这些是基因 无眼(EY)、正弦眼球(SO)、无眼(EYA)和腊肠(DAC)。这些 基因是眼睛发育所必需的，可以诱导其他组织形成眼睛， 并通过在基因水平上的相互作用连接在基因网络中 蛋白质-蛋白质接触和转录调控。为了生成一个 对建立眼睛所涉及的遗传回路的更完整的描述 在果蝇中，我们建议识别其他参与其中的基因 并研究它们与已知基因的关系。我们是 寻求四种不同的方法来确定与此相关的新因素 进程。在前两种方法中，我们使用前面标识的 用于识别新因子的眼睛规范基因网络的组成部分 通过蛋白质-DNA和蛋白质-蛋白质相互作用。另外两个是基于 基因筛查以确定眼睛所需或足够的基因活动 在眼盘(正常眼)或其他组织(异位眼)内诱导。 已确定的基因的详细分子和功能特征 将使用这些方法。通过组合前锋 遗传和反向遗传方法、分子遗传分析和异位 表达研究，我们将剖析这些新的因子在 眼组织规范并在已有的上下文中定义其角色 有趣的是，尽管存在显著的差异，但确定了遗传途径 在苍蝇和人眼之间的结构和功能上， 这种遗传网络似乎在进化上是保守的。几个相关的 已经在老鼠和人类中发现了包括Pax6和Multiple Si6在内的基因， 已发现EYA和DAC基因以及其中一些基因调节眼睛 脊椎动物的发育。因此，失眼的Pax6基因突变会导致无虹膜 人，小鼠的小眼睛表型，和人类的无眼表型 果蝇。此外，Pax6和Six3已经被证明可以诱导眼睛结构 (晶状体和视网膜)当在非洲爪哇和Medaka鱼中异位表达时， 这表明分子水平上的同源性可能延伸到 眼睛发育过程中的功能保护。广泛的保护 参与眼睛发育早期的分子因素表明 对果蝇的研究将提供对遗传机制的见解 控制哺乳动物的眼睛发育。

DESCRIPTION (Verbatim from applicant's abstract): The long-term objective of this proposal is to gain a better understanding of the genetic control of eye-tissue determination in Drosophila. Several genes that play important roles in this process have been identified in recent years. These are the genes eyeless (ey), sine oculis (so), eyes absent (eya) and dachshund (dac). These genes are required for eye development, can induce other tissues to form eyes, and are linked in a gene network by interactions at the level of protein-protein contacts and transcriptional regulation. In order to generate a more complete picture of thegenetic circuitry involved in establishing eye identity in the fruit fly, we propose to identify additional genes involved in this process and study their relationship to the genes already known. We are pursuing four different approaches to identify novel factors involved in this process. In the first two approaches, we make use of previously identified components of the eye-specification gene network to identify novel factors through protein-DNA and protein-protein interactions. The other twoarebased on genetic screens to identify gene activities required or sufficient for eye induction within theeye disc (normal eyes) or in other tissues (ectopic eyes). A detailed molecular and functional characterization of the genes identified using these approaches will be carried out. Through a combination of forward genetic and reverse genetic approaches, molecular genetic analysis and ectopic expression studies, we will dissect the function of these novel factors in eye-tissue specification and define their role in the context of the already identified genetic pathways, Interestingly, despite the significant differences in structure and function between the fly and human eyes, the components of this genetic network appear to be evolutionarily conserved. Several related genes have been identified in mouse and humans including Pax6 and multiple Six, Eya and Dac genes and some of these genes have been found to regulate eye development in vertebrates. Thus, mutations in eyeless Pax6 cause Aniridia inhumans, the Small eye phenotype in mice, and the eyeless phenotype in Drosophila. Moreover, Pax6 and Six3 have been shown to induce eye structures (lens and retina) when ectopically expressed in Xenopus and Medaka fish, indicating that the homology at the molecular level may extend to a conservation of function in eye development. The extensive conservation of molecular factors involved in the early steps of eye development indicates that work in Drosophila will provide insights into the genetic mechanisms controlling mammalian eye development.