This project will contribute to our understanding of gradient sensing, the ability of cells to sense small differences in chemical concentration across their surfaces, and thereby locate the source of the stimulus. This phenomenon is essential for the development and health of all organisms. The principal investigator uses yeast cells as a model to study the molecular mechanisms underlying gradient sensing, which are thought to be broadly applicable to cells in more complex organisms as well. During this project period, the principal investigator and his postdoctoral scientist will mentor select biology students from nearby Malcolm X College (MXC), one of the City Colleges of Chicago, in an effort to enhance their chances of graduating from a four-year institution with a BS in a STEM field. The proposed undergraduate research and mentoring program is designed to inspire, instruct, advise, and support underrepresented students who may be interested in a STEM career. The investigation will also provide students and the postdoctoral scientist with interdisciplinary training through interactions with collaborators who are experts in diverse areas. Because the project is at the interface of math and biology, researchers on each team will gain a better understanding of the methods used by those in the other discipline.
The best-known gradient-stimulated cellular outputs, chemotaxis (directed cell movement), and chemotropism (directed cell growth), are required for a wide range of biologic processes. Although they ultimately exhibit quite different behavior, chemotactic and chemotropic cells face similar challenges: the responding cell must sense small differences in chemical concentration across its surface, determine the direction of the gradient source, and polarize its cytoskeleton toward it. The mating response of the budding yeast S. cerevisiae is chemotropic: mating cells interpret complex pheromone gradients and polarize their growth in the direction of the closest partner. Like many chemotaxing cells, yeast use G protein-coupled receptors to detect mating pheromone secreted by potential partners and thereby direct their growth toward the nearest pheromone source. The goal of this project is to understand how the chemotropic growth site is established before polarization of the cytoskeleton, and how the cell responds to changes in gradient direction. Various models have been proposed to explain how yeast interpret shallow pheromone gradients in vivo, but none satisfactorily answers the fundamental and long-standing question: how do the cells switch from the default polarity site they use for cell division to establish a chemotropic site, despite a near zero signal-to-noise ratio? Based on discoveries made during a previous project, the principal investigator proposed a model that answers this question. The working hypothesis is that mating yeast initially ignore the pheromone gradient, as they first colocalize and concentrate signaling and trafficking proteins at the default site, building a "gradient tracking machine" (GTM). Once assembled, the GTM moves along the plasma membrane to the point of maximal pheromone concentration, where it marks the chemotropic site. The priorities of this investigation are to learn how the GTM is assembled, how it moves to the chemotropic site, and how it steers chemotropic growth in response to changes in gradient direction. These questions will be answered using imaging, genetic, optogenetic, biochemical, and computational approaches, leading to a deeper understanding of chemical gradient sensing. Because little is known about how gradient-aligned cell polarity is established during the chemotropic responses of other eukaryotes, general principles are likely to emerge that will broadly influence the study of chemotropic phenomena. Moreover, many of the questions posed in this investigation are pertinent to other transmembrane signaling systems, and the findings are expected to reveal generally relevant mechanisms.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
