Migration is a fundamental cellular behavior that is critical for numerous processes including organ formation during embryogenesis, tissue homeostasis in the adult, and sexual reproduction during the journey of sperm to egg. The goal of this project is to dissect the cellular and molecular mechanisms by which individual migrating cells sense their environment, respond by altering their motility, and communicate with one another as they do so. We are taking advantage of a highly tractable system for studying the genetic control of these processes: sperm of the nematode C. elegans. Nematode sperm move by crawling, similar to many other motile cell types, and they must compete in order to migrate and fertilize oocytes. This system thus provides a platform to study not only the mechanisms that control motility, but also how differences between migrating cells affect their ability to entr and occupy a target tissue. Since C. elegans is small and transparent, migration, competition, and its outcome can all be directly observed within living animals, and many tools exist for manipulating the genetic makeup of migratory cells and their surroundings. Utilizing these features, we have developed tools for imaging cell behaviors and identified both a kinase-like protein, COMP-1, that functions in sperm, as well as a prostaglandin signaling pathway in substrate tissue that regulate the ability of sperm to migrate and compete. We now propose to determine how these cell-intrinsic and cell-extrinsic pathways intersect to control migration and competition and to define additional regulators of these processes.
In Aim 1, we will determine the role of COMP-1 in regulating cell behaviors important for sperm migration, localization and competition, both in C. elegans and other nematodes.
In Aim 2, we will identify the contribution of sperm-gonadal signaling pathways and sperm-substrate interactions within recipient tissues to regulating sperm migration, localization, and competition.
In Aim 3, we will continue a successful genetic screen to identify new regulators of sperm migration, localization, and competition. Our studies will (1) reveal general paradigms for understanding how specific migratory behaviors affect the ability of migrating cells to populate a target tissue, independent of signals that may vary among tissue types; (2) provide direct insight into prostaglandin signaling pathways, which are of known importance for human health and disease through roles in inflammation, fertility, and other processes; and (3) characterize a candidate target for anthelmintic drugs to treat nematode parasites pests, which infect upward of 1 billion individuals worldwide along with agriculturally important animals and plants, resulting in immense burdens on human health and economies.
There are many instances where individual cells must migrate to perform their function: for example, the formation of organs during embryonic development, the repair of damaged tissues during adulthood, and the journey of sperm to egg during reproduction. The success of this process depends on the ability of individual cells to receive and interpret signals from their environment and other cells, and in some cases cells compete with one another to reach their target. We are using C. elegans sperm as a model cell type to analyze the intercellular and intracellular mechanisms involved in competition among motile cells to migrate into and colonize a target tissue.