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

项目摘要 分泌的信号蛋白如何在细胞生物学水平上协调动物的发育和维持 对成人组织了解甚少。这里描述的研究计划旨在阐明信号如何 分子水平的机制与细胞结构和行为相结合，以调节细胞内的信号传导。 空间和时间这种知识将有助于深入了解发展的基本机制， 体内平衡它还将对人类健康产生影响，因为许多相同的信号通路 与癌症有关，是组织工程和再生医学的关键参与者。的广泛目标 在未来的五年里，这个项目将剖析细胞间相互作用的基本细胞生物学机制。 发展过程中的信号。细胞通常使用分泌的信号蛋白以一系列的方式进行通信。 距离调节模式和分化沿着与细胞行为，如迁移， 形态发生这些蛋白质如何在细胞之间移动到达目的地并激活信号 仍然是未知的。我们将使用蠕虫C。线虫作为一个易处理的模型来研究细胞 这些过程的生物学基础。C. elegans是一个强大的系统， 由于基因组工程的速度和效率，用于活成像的极好特性，以及一系列 功能操作的方法。拟议的工作建立在以前的努力， 称为Wnts的信号蛋白用于在细胞之间分散的机制， 利用先进的细胞生物学方法研究发育信号的其他方面。我们 未来几年的目标是阐明：（1）神经在长距离Wnt信号传导到非神经细胞中的功能 （2）来自细胞信号传导途径的空间输入如何与细胞动力学相结合 引导细胞迁移;（3）Wnt和其他胞外蛋白之间的相互作用如何控制Wnt 蔓延为了实现这些目标，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来询问空间发育机制， 和时间精度。总之，我们的努力将为细胞生物学提供新的和机械的见解。 动物发展的基础，并建立一个独特的和持续的贡献框架。

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.