Regulation of dynamic actin networks during epithelial morphogenesis

项目摘要 胚胎发育需要作为胚胎的上皮片的动态重塑 在形态发生过程中自我转化。了解这些事件具有重要的意义 了解人类常见的先天缺陷和常见癌症。我们的目标是 对胚胎形态发生运动的多学科综合分析 详细的结构分析、单分子生物物理学、遗传学和体内动态分析， 以线虫胚胎为模型系统。我们最近的重点放在两个大的领域 细胞骨架调节：机械转导发生的机制通过 钙粘附素/连环蛋白复合体在形态发生中的作用及上皮细胞的细胞机制 由基底侧向运动驱动的重排。我们将在这里继续强调这些重点： 1.确定形态发生过程中α-连环蛋白的机械转导机制 将研究sRGP-1/srGAP与HMP-1/α-连环蛋白的张力依赖性相互作用 SRGP-1招募如何正向调节钙粘素复合体的功能。 2.明确张力状态下连接肌动蛋白网络的自我修复机制 形态发生：我们将测试一个模型，在该模型中，不同的LIM结构域包含重复 (LCR)蛋白通过连接的近端F-肌动蛋白网络稳定不同的亚结构 处于紧张状态下，以防自伤。 3.明确上皮细胞中肌动蛋白的局部聚合机制 重排：我们将使用综合方法来确定CRML-1/CARMIL如何 通过对带刺末端肌动蛋白封端机械的影响，负向调节运动性。 4.确定促进细胞极化运动的局部信号通路 重排：我们将确定其他信号成分如何调节上皮细胞 细胞重排。 作为这些研究的结果，我们将对粘连连接如何能够 在生物体中承受和应对紧张，我们将阐明一条新的途径 通过基底侧突起活动调节细胞嵌入。每个项目都有广泛的 对理解对人类不同细胞事件至关重要的过程的启示 发展和疾病。

Project Summary Embryonic development requires the dynamic remodeling of epithelial sheets as the embryo transforms itself during morphogenesis. Understanding these events has important implications for understanding common human birth defects and common cancers. Our aim is a multidisciplinary, integrated analysis of morphogenetic movements in embryos that unites detailed structural analysis, single-molecule biophysics, genetics, and dynamic in vivo analysis, using the C. elegans embryo as a model system. Our recent focus has been in two broad areas of cytoskeletal regulation: the mechanisms by which mechanotransduction occurs through the cadherin/catenin complex during morphogenesis, and cellular mechanisms of epithelial cell rearrangement driven by basolateral motility. We will continue these emphases here: 1. Define mechanisms of α-catenin mechanotransduction during morphogenesis: We will examine the tension-dependent interaction of SRGP-1/srGAP with HMP-1/α-catenin and how SRGP-1 recruitment positively modulates cadherin complex function. 2. Define mechanisms of self-healing of junctional actin networks under tension during morphogenesis: We will test a model in which different LIM-domain containing repeat (LCR) proteins stabilize different substructures with the junctional proximal F-actin network under tension to prevent self-injury. 3. Define mechanisms of local actin polymerization in during epithelial cell rearrangement: We will use an integrated approach to determine how CRML-1/CARMIL negatively regulates motility via effects on the barbed end actin capping machinery. 4. Define local signaling pathways that promote polarized motility during cell rearrangement: We will determine how additional signaling components regulate epithelial cell rearrangement. As a result of these studies, we will gain new insight into how adherens junctions are able to withstand and respond to tension in a living organism, and we will elucidate a novel pathway regulating cell intercalation via basolateral protrusive activity. Each project has widespread implications for understanding processes crucial for diverse cellular events during human development and disease.