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: 10398238
• 负责人: Jeremy Nance
• 金额: $ 63.33万
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398238
• 关键词: Address; Apical; Biological Models; Blood capillaries; Caenorhabditis elegans; Cannibalism; Cell Communication; Cell physiology; Cells; Cellular biology; Complex; Congenital Abnormality; Cytoplasm; Cytoplasmic Tail; Development; Disease; E-Cadherin; Embryo; Embryonic Development; Ensure; Epithelial Attachment; Event; Foundations; Germ Cells; Goals; Health; Human; Human Development; Image; Intestines; Invaded; Learning; Link; Lobe; Malignant Neoplasms; Membrane; Mitochondria; Molecular; Nematoda; Organ; PAC1 phosphatase; Proteins; Research; Role; Shapes; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Structure of primordial sex cell; System; Testing; Tissues; Tube; Vesicle; genetic analysis; human disease; in vivo Model; insight; polarized cell; programs; recruit; rho GTPase-activating protein; stem cells

PROJECT SUMMARY Interactions between cells direct many aspects of embryonic development. The long-term goal of our research program is to learn how cell interactions determine the shape, organization, and function of developing cells, tissues, and organs. Using C. elegans as an in vivo model where genetic analysis, live imaging and cell biology can be combined, we have developed several simple experimental systems to investigate how cell interactions regulate conserved morphogenetic events. The specific goals of this proposal are to use these model systems to fill key gaps in understanding how cells develop polarity, how small tubes form, and how niche cell interactions regulate germ cell biology. In one project, we are investigating how cell contact induces apicobasal polarity. This project addresses two outstanding questions – how cell contacts induce the PAR protein asymmetries that polarize cells, and how PAR proteins elaborate other intracellular asymmetries. We previously discovered that E-cadherin signals to induce polarity by recruiting the RhoGAP PAC-1, which triggers PAR protein asymmetries. We will extend these findings by uncovering new molecular links connecting PAC-1 to the E-cadherin cytoplasmic tail, by identifying additional signaling pathways that contribute to polarization, and by investigating how the PAR protein aPKC induces the formation of epithelial junctions. In a second project, we are investigating how small tubes develop. Small tubes such as capillaries can form in the cytoplasm of a cell when vesicles are targeted to an invading apical domain. It is unclear how vesicles are targeted to this site to form intracellular tubes. We are addressing this question by determining how the excretory cell forms an intracellular tube. We found that PAR proteins localize the exocyst vesicle- tethering complex to direct vesicle fusion events to the invading apical domain, and will extend these findings by investigating how PAR proteins recruit the exocyst and how the initial site for tube formation is specified. In a final project, we are determining how niche cell interactions influence germ cell development. Niche cells wrap membrane extensions around germ cells and stem cells but the significance of these interactions is poorly understood. We discovered that primordial germ cells (PGCs) extend large protrusions that are wrapped and cannibalized by intestinal cells, eliminating most PGC mitochondria. We will determine the importance of PGC lobe cannibalism, testing the hypothesis that it helps ensure the health of germline mitochondria. Together, our findings will reveal new, basic insights into how cell interactions guide critical developmental events, providing a foundation for understanding the contribution of cell interactions in human development and disease.

项目摘要 细胞之间的相互作用指导胚胎发育的许多方面。我们研究的长期目标 程序是了解细胞相互作用如何决定发育单元格的形状，组织和功能， 使用秀丽隐杆线虫作为遗传分析，活成像和细胞生物学的体内模型 可以组合，我们开发了几个简单的实验系统，以研究细胞相互作用 调节组成形态发生事件。该建议的具体目标是使用这些模型系统 为了填补关键空白，了解细胞如何发展极性，小管的形成方式以及小众细胞如何形成 相互作用调节生殖细胞生物学。 在一个项目中，我们正在研究细胞接触如何诱导腹骨极性。该项目解决 两个突出的问题 - 细胞接触如何诱导细胞极化的PAR蛋白不对称，以及 蛋白质如何详细说明其他细胞内不对称。我们以前发现E-钙粘蛋白信号 通过募集Rhogap Pac-1诱导极性，这会触发PAR蛋白不对称。我们将扩展 通过发现将PAC-1与E-钙粘蛋白细胞质尾部连接到E-钙粘蛋白的尾巴的新分子链接，通过 确定有助于极化的其他信号通路，并通过研究PAR 蛋白APKC诱导上皮连接的形成。 在第二个项目中，我们正在研究小管的发展方式。小管，例如毛细管可以 当蔬菜靶向入侵的顶端域时，在细胞的细胞质中形成。目前尚不清楚如何 囊泡针对该部位以形成细胞内管。我们通过确定来解决这个问题 极端细胞如何形成细胞内管。我们发现蛋白质定位于外囊蔬菜 - 将复合物绑定到囊泡融合事件到入侵的顶端结构域，并将扩展这些发现 通过研究PAR蛋白如何募集外囊肿以及如何指定试管形成的初始位点。 在最终项目中，我们正在确定利基细胞相互作用如何影响生殖细胞的发育。利基 细胞包裹生殖细胞和干细胞周围的膜延伸，但这些相互作用的重要性是 理解不佳。我们发现原始生殖细胞（PGC）延伸了包裹的大突起 并被肠细胞蚕食，消除了大多数PGC线粒体。我们将确定重要性 PGC叶蚕食，检验了以下假设：它有助于确保种系线粒体的健康。 我们的发现将共同揭示有关细胞相互作用如何指导关键发展的新的基本见解 事件，为理解细胞相互作用在人类发展中的贡献提供基础 和疾病。