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

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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.