Head Region Development of C. elegans

描述(申请人提供)：表皮形态发生是许多 动物发育，然而上皮运动的分子机制是 人们对此仍知之甚少。我们对线虫的表皮进行了研究。 线虫作为上皮形态发生的多个方面的简单模型。我们的 长期目标是确定调节表皮的蛋白质。 形态发生。我们已经确定了在神经细胞中起作用的基因。 调控线虫表皮形态发生的信号。其中包括一种Eph 受体酪氨酸激酶(VAB-1)，一种肾上腺素配体3.我们的遗传分析 显示了Eph信令构成了部分冗余网络的一部分 VAB-1受体(EFN-L/VAB-2)和LAR型受体酪氨酸磷酸酶 调控线虫形态发生的PTP信号通路。我们将分析 Eph信号如何在形态发生中调节细胞行为 为了更好地了解Eph信号通路的机制并阐明 它们在体内的形态发生中起作用。我们有三个具体目标。(1)我们 将表征一种发散的线虫Ephin，EFN-4。EFN-4基因突变 影响形态发生。我们将测试EFN-4是否是VAB-1的配体 受体以及它是否调节其他线虫伊弗林的作用。我们会 同时寻找新的EFN-4结合蛋白。(2)我们先前的工作表明 Eph信号转导功能与其他两条途径部分冗余。在屏幕上 为了确定这种途径的新组成部分，我们已经确定了一个基因座，该基因座 显示了与VAB-1的合成致死相互作用。为了更好地理解 与Eph信号相互作用的途径我们将描述这个基因和 确定其他与VAB-1相互作用的基因。(3)抑制子分析可以识别 可能无法通过直接遗传找到的信号通路的组成部分 屏幕。我们已经确定了VAB-1功能丧失突变的抑制因子和 将通过基因和分子克隆来分析其中一个抑制子。我们 还将生成功能增益(构造激活)版本 VAB-1，并将其用于新的抑制器屏幕。Eph信号在其中扮演着多种角色 在神经和血管发育中，并与肿瘤的发生有关。 这些目的是利用线虫可用的遗传方法来 研究Eph信号及其在神经和表皮形态发生中的作用。

DESCRIPTION (provided by applicant): Epidermal morphogenesis underlies much of animal development, yet the molecular mechanisms of epithelial movements are still poorly understood. We study the epidermis of the nematode Caenorhabditis elegans as a simple model for many aspects of epithelial morphogenesis. Our long-term goal is to identify the proteins that regulate epidermal morphogenesis. We have identified genes that function in neuronal cell signaling to regulate C. elegans epidermal morphogenesis. These include an Eph receptor tyrosine kinase (VAB-1), an ephrin ligand 3. Our genetic analysis showed that Eph signaling forms part of a network of partly redundant for the VAB-1 receptor (EFN-l/VAB-2), and the LAR-type receptor tyrosine phosphatase PTP- signaling pathways that regulate C. elegans morphogenesis. We will analyze how Eph signaling functions to regulate cell behaviors in morphogenesis, both to better understand the mechanisms of Eph signaling pathways and to elucidate their in vivo function in morphogenesis. We have three specific aims. (1) We will characterize a divergent C. elegans ephrin, EFN-4. Mutations in EFN-4 affect morphogenesis. We will test whether EFN-4 is a ligand with the VAB-1 receptor and whether it modulates effects of other C. elegans ephrins. We will also search for novel EFN-4 binding proteins. (2) Our earlier work showed that Eph signaling function is partly redundant with two other pathways. In screens to identify new components of such pathways, we have identified a locus that shows synthetic-lethal interactions with vab-1. To better understand the pathways that interact with Eph signaling we will characterize this gene and identify other vab-1-interacting genes. (3) Suppressor analysis can identify components of signaling pathways that may not be found by direct genetic screens. We have identified suppressors of vab-1 loss-of-function mutations and will analyze one of these suppressors genetically and by molecular cloning. We will also generate gain-of-function (constitutively activated) versions of VAB-1 and use these in new suppressor screens. Eph signaling plays many roles in neural and vascular development and has been implicated in tumorigenesis. These aims take advantage of genetic approaches available in C. elegans to study Eph signaling and its roles in neural and epidermal morphogenesis.