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.

项目总结 细胞之间的相互作用指导着胚胎发育的许多方面。我们研究的长期目标是 课程是学习细胞相互作用如何决定发育中细胞的形状、组织和功能， 组织和器官。使用线虫作为体内模型，进行遗传分析、活体成像和细胞生物学 可以结合在一起，我们开发了几个简单的实验系统来研究细胞相互作用 调节保守的形态发生事件。本提案的具体目标是使用这些模型系统 填补在理解细胞如何形成极性、如何形成小管以及如何形成利基细胞方面的关键空白 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心尖基极。本项目致力于 两个悬而未决的问题--细胞接触如何导致使细胞极化的PAR蛋白不对称，以及 PAR蛋白如何阐述其他细胞内的不对称性。我们之前发现E-钙粘素信号 通过招募RhoGAP PAC-1来诱导极性，从而触发PAR蛋白不对称。我们将延长 这些发现是通过发现连接PAC-1和E-钙粘蛋白细胞质尾巴的新的分子连接，通过 确定导致极化的其他信号通路，并调查PAR如何 蛋白aPKC诱导上皮连接的形成。 在第二个项目中，我们正在研究细小的管子是如何发展的。像毛细血管这样的小管子可以 当小泡以侵入的顶端区域为靶点时，在细胞质中形成。目前还不清楚是如何 囊泡被定位到这个部位，形成细胞内的管子。我们正在通过确定以下方式来解决这个问题 排泄物细胞是如何形成细胞内管的。我们发现PAR蛋白定位于外囊泡- 系留复合体将囊泡融合事件定向到侵袭的顶端区域，并将扩展这些发现 通过研究PAR蛋白如何招募外囊以及如何指定管子形成的初始位置。 在最后一个项目中，我们正在确定利基细胞相互作用如何影响生殖细胞发育。利基市场 细胞将膜延伸包裹在生殖细胞和干细胞周围，但这些相互作用的意义是 人们对此知之甚少。我们发现原始生殖细胞(PGC)延伸出被包裹的大突起 并被肠道细胞吞噬，消除了大部分PGC线粒体。我们将确定以下内容的重要性 PGC叶自相残杀，验证了它有助于确保生殖系线粒体健康的假设。 总之，我们的发现将揭示细胞相互作用如何引导关键发育的新的、基本的见解 事件，为理解细胞相互作用在人类发育中的贡献提供了基础 和疾病。