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（由适用提供）：细胞之间的相互作用会影响胚胎发育的许多关键方面。该建议的广泛目标是确定细胞相互作用如何确定胚胎发生过程中细胞，组织和器官的形状和组织。使用线虫秀丽隐杆线虫作为一个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，以研究细胞相互作用如何调节随着组织和器官的发展，如何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在早期胚胎细胞中诱导腹骨极性。我们最近表明，粘合蛋白E-钙粘着蛋白通过将对称性的Rhogap Pac-1募集到细胞接触位点来诱导极性，并且还发现未识别的冗余途径有助于极化。我们将通过确定e-钙粘着蛋白如何在细胞接触处积累，研究E-钙粘着蛋白相互作用的蛋白α-catenin如何募集PAC-1以及鉴定冗余途径的成分，从而扩展这些发现，从而扩展这些发现。在第二个项目中，我们研究了极性蛋白如何调节上皮细胞连接和管的形成。我们先前表明，粘附连接的成熟是必需的。为了确定它是如何做到的，我们将克隆和表征突变，这些突变是我们在遗传相互作用筛选中鉴定出的，影响连接完整性。另外，我们将确定PAR蛋白和外囊综合体如何识别流体结构域并将囊泡运输直接运输到这些位点以延伸细胞内管。在第三个项目中，我们研究了我们发现的新型细胞形态发生形式的机制 - 当内胚层细胞积极咬合并消化原始生殖细胞（PGC）扩展的大叶时，发生了一种食性事件。这种形式形式可能在其他系统中被忽略了，我们假设它对于生殖细胞发育至关重要。我们发现Rho GTPase RAC诱导肌动蛋白积聚在PGC裂片的底部，并且是内胚层细胞的这些结构科学所必需的。我们将确定RAC和肌动蛋白在Lobe Science中的功能，我们将表征几个其他基因，这些基因在遗传筛选中确定，这对于叶科学至关重要。总之，我们的发现将揭示有关细胞，组织和组织在发育过程中如何改变形状并将其组织成功能单位的新的基本见解，并将为理解以缺陷的细胞相互作用（例如癌症）为特征的疾病的分子基础提供基础。