Dissecting the cell-biological foundations of developmental cell signaling in a living animal

项目总结 分泌的信号蛋白如何在细胞生物水平上协调动物的发育和维持 人们对成体组织知之甚少。这里描述的研究计划试图阐明信号是如何 分子水平上的机制与细胞结构和行为相结合，以调节信号转导 空间和时间。这些知识将提供对发展和发展的基本机制的见解 动态平衡。它还将对人类健康产生相关影响，因为许多相同的信号通路 与癌症有牵连，是组织工程和再生医学的关键参与者。的宏伟目标 在接下来的五年里，这个计划将剖析构成细胞-细胞的基本细胞生物学机制。 在发育过程中发出信号。细胞通常使用分泌的信号蛋白在一系列 调节图案化和分化以及细胞行为的距离，如迁移和 形态发生。这些蛋白质如何在细胞之间移动以到达它们的目的地并激活信号 在很大程度上仍不为人所知。我们将使用线虫作为一个易于处理的模型来研究细胞 活体动物体内这些过程的生物学基础。线虫是一个解开机制的强大系统 由于基因组工程的速度和效率，现场成像的卓越特性，以及一系列 函数操作的方法。拟议的工作建立在先前的努力基础上，这些努力确定了必要的 被称为WNTS的信号蛋白用来在细胞之间扩散的机制和已建立的实验 使用先进的细胞生物学方法研究发育信号的其他方面的系统。我们的 未来几年的目标是阐明：(1)神经在长距离中的功能，Wnt信号传递给非神经 细胞发育过程中的细胞；(2)细胞信号通路的空间输入如何与细胞动力学整合 以引导细胞迁移；以及(3)WNT与其他胞外蛋白之间的相互作用如何控制WNT 正在扩散。为了实现这些目标，我们将使用一套方法，包括超分辨率实时成像， 基因组工程，和体内细胞生物学方法，以空间询问发育机制 和时间的精确度。我们的共同努力将为细胞生物学提供新的和机械性的见解 建立动物发展基地，并建立一个独特和可持续的贡献框架。

Project summary How secreted signaling proteins act at a cell-biological level to orchestrate animal development and maintain adult tissues is poorly understood. The research program described here seeks to elucidate how signaling mechanisms at the molecular level are integrated with cell architectures and behaviors to regulate signaling in space and time. Such knowledge will provide insights into essential mechanisms of development and homeostasis. It will also have impacts relevant to human health as many of the same signaling pathways are implicated in cancers and are key players in tissue engineering and regenerative medicine. The broad goal of this program over the next five years is to dissect fundamental cell biological mechanisms that underlie cell-cell signaling during development. Cells often use secreted signaling proteins to communicate at a range of distances to regulate patterning and differentiation along with cellular behaviors such as migration and morphogenesis. How these proteins move between cells to reach their destinations and activate signaling remains largely unknown. We will use the worm C. elegans as a tractable model to investigate the cell biological bases for these processes in a living animal. C. elegans is a powerful system to unravel mechanisms due to the speed and efficiency of genome engineering, superb characteristics for live imaging, and a range of methods for functional manipulations. The proposed work builds on prior efforts that identified essential mechanisms that signaling proteins called Wnts use to disperse between cells and established experimental systems to investigate other aspects of developmental signaling using advanced cell biology methods. Our goals in the coming years are to elucidate: (1) functions for nerves in long distance Wnt signaling to non-neural cells during development; (2) how spatial inputs from a cell signaling pathway are integrated with cell dynamics to guide cell migration; and (3) how interactions between Wnts and other extracellular proteins control Wnt spreading. Towards these goals, we will use a suite of approaches, including super-resolution live imaging, genome engineering, and in vivo cell biology methods to interrogate developmental mechanisms with spatial and temporal precision. Together, our efforts will provide novel and mechanistic insights into the cell biological bases of animal development and build a framework for unique and sustained contributions.