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: 10614459
• 负责人: Jeremy Nance
• 金额: $ 26.34万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614459
• 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.

项目概要 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。 计划的目的是了解细胞相互作用如何决定发育细胞的形状、组织和功能， 使用秀丽隐杆线虫作为体内模型，进行遗传分析、实时成像和细胞生物学。 可以结合起来，我们开发了几个简单的实验系统来研究细胞如何相互作用 该提案的具体目标是使用这些模型系统。 填补理解细胞如何形成极性、小管如何形成以及生态位细胞如何形成的关键空白 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顶端基底极性。 两个悬而未决的问题——细胞接触如何诱导导致细胞极化的 PAR 蛋白不对称性，以及 PAR 蛋白如何阐述其他细胞内不对称性我们之前发现 E-钙粘蛋白信号。 通过招募 RhoGAP PAC-1 来诱导极性，这会触发 PAR 蛋白不对称性。 这些发现通过揭示连接 PAC-1 与 E-钙粘蛋白细胞质尾部的新分子联系来实现 有助于极化的其他信号通路，并通过研究 PAR 如何 蛋白 aPKC 诱导上皮连接的形成。 在第二个项目中，我们正在研究毛细管等小管是如何发育的。 当囊泡靶向入侵的顶端结构域时，在细胞的细胞质中形成，目前尚不清楚。 囊泡靶向该位点形成细胞内管，我们通过确定来解决这个问题。 我们发现 PAR 蛋白定位于外囊泡 - 排泄细胞如何形成细胞内管。 束缚复合物将囊泡融合事件引导至入侵的顶端区域，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形成的初始位点。 在最终项目中，我们正在确定生态位细胞相互作用如何影响生殖细胞发育。 细胞将生殖细胞和干细胞周围的膜延伸包裹起来，但这些相互作用的意义在于 我们对原始生殖细胞（PGC）的延伸了解甚少。 并被肠道细胞蚕食，消除大部分 PGC 线粒体。我们将确定其重要性。 PGC 叶同类相食，检验其有助于确保种系线粒体健康的假设。 总之，我们的研究结果将揭示细胞相互作用如何指导关键发育的新的基本见解 事件，为理解细胞相互作用在人类发展中的贡献奠定了基础 和疾病。