The role of cell interactions in shaping development

细胞相互作用在塑造发育中的作用

• 批准号: 9912781
• 负责人: Jeremy Nance
• 金额: $ 59.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912781
• 关键词: Actins; Adherens Junction; Adhesions; Affect; Bite; Caenorhabditis elegans; Cell Communication; Cells; Complex; Congenital Abnormality; Development; Disease; E-Cadherin; Embryo; Embryonic Development; Endoderm Cell; Epithelial Cell Junction; Event; Foundations; Genes; Genetic; Genetic Screening; Germ Cells; Goals; Human; Image; Lobe; Malignant Neoplasms; Modeling; Molecular; Morphogenesis; Mutation; Nematoda; Organ; PAC1 phosphatase; Pathway interactions; Proteins; Role; Shapes; Site; Structure; Structure of primordial sex cell; System; Tissues; Tube; Vesicle; alpha catenin; base; blastomere structure; genetic analysis; in vivo Model; insight; novel; polarized cell; protein E; public health relevance; recruit; rho GTP-Binding Proteins; rho GTPase-activating protein; trafficking

 DESCRIPTION (provided by applicant): Interactions between cells influence many critical aspects of embryonic development. The broad goal of this proposal is to determine how cell interactions determine the shape and organization of cells, tissues, and organs during embryogenesis. Using the nematode C. elegans as an in vivo model where genetic analysis and live imaging can be combined, we have developed several simple experimental systems to investigate how cell interactions regulate conserved morphogenetic events as tissues and organs develop. In one project, we investigate how cell contacts induce apicobasal polarity in early embryonic cells. We recently showed that the adhesion protein E-cadherin induces polarity by recruiting the symmetry-breaking RhoGAP PAC-1 to cell contact sites, and also discovered that an unidentified redundant pathway contributes to polarization. We will extend these findings by determining how E-cadherin accumulates at cell contacts, investigating how the E-cadherin interacting protein α-catenin recruits PAC-1, and identifying components of the redundant pathway that polarizes cells independently of E-cadherin. In a second project, we investigate how PAR polarity proteins regulate the formation of epithelial cell junctions and tubes. We showed previously that PAR-6 is required for the maturation of adherens junctions. To determine how it does so, we will clone and characterize mutations, which we identified in a genetic interaction screen, that affect junction integrity. Separately, we will determine how PAR proteins and the exocyst complex recognize lumenal domains and direct vesicle trafficking to these sites to extend intracellular tubes. In a third project, we investigate the mechanisms of a novel form of cellular morphogenesis we discovered - a cannibalistic event that occurs when endodermal cells actively bite off and digest large lobes extended by primordial germ cells (PGCs). Such a form of morphogenesis is likely to have been overlooked in other systems, and we hypothesize that it is critical for germ cell development. We found that the Rho GTPase Rac induces actin to accumulate at the base of PGC lobes and is required for the scission of these structures by endodermal cells. We will determine how Rac and actin function in lobe scission, and we will characterize several additional genes, which we identified in a genetic screen, that are essential for lobe scission. Together, our findings will reveal new, basic insights into how cells, tissues, and organs change shape and organize into functional units during development, and will provide a foundation for understanding the molecular basis of diseases characterized by defective cell-cell interactions, such as cancer.

 描述（由申请人提供）：细胞之间的相互作用影响胚胎发育的许多关键方面，该提案的主要目标是利用线虫 C 来确定细胞相互作用如何决定细胞、组织和器官的形状和组织。线虫作为一种可以结合遗传分析和实时成像的体内模型，我们开发了几个简单的实验系统来研究细胞相互作用如何在组织和器官发育过程中调节保守的形态发生事件。在一个项目中，我们研究了细胞接触如何诱导。我们最近表明，粘附蛋白 E-钙粘蛋白通过将对称性破坏的 RhoGAP PAC-1 招募到细胞接触位点来诱导极性，并且还发现了一条未识别的冗余途径有助于极化。通过确定 E-钙粘蛋白如何在细胞接触处积聚、研究 E-钙粘蛋白相互作用蛋白 α-连环蛋白如何募集 PAC-1 以及识别冗余途径的组成部分来发现结果在第二个项目中，我们研究了 PAR 极性蛋白如何调节上皮细胞连接和管的形成，我们之前表明 PAR-6 是粘附连接成熟所必需的。为此，我们将克隆和表征我们在遗传相互作用筛选中发现的影响连接完整性的突变，另外，我们将确定 PAR 蛋白和外囊复合物如何识别腔域并进行指导。在第三个项目中，我们研究了我们发现的一种新型细胞形态发生的机制，即内胚层细胞主动咬住并消化由原始生殖细胞延伸的大叶时发生的同类相食事件。这种形式的形态发生在其他系统中可能被忽视，我们发现它对于生殖细胞发育至关重要，我们发现 Rho GTPase Rac 诱导肌动蛋白形成。积累在 PGC 叶的基部，并且是内胚层细胞分裂这些结构所必需的。我们将确定 Rac 和肌动蛋白在叶分裂中的功能，并且我们将表征我们在遗传筛选中鉴定的几个额外基因，它们是总之，我们的研究结果将揭示细胞、组织和器官在发育过程中如何改变形状和组织成功能单元的新的基本见解，并将为理解以缺陷细胞为特征的疾病的分子基础奠定基础。细胞相互作用，例如癌症。