The development of cell shape and three-dimensional organization (cellular morphogenesis) is a process of fundamental importance in cellular and developmental biology. Defects in cellular morphogenesis are also implicated in disease states such as birth defects and cancer. The long-term goal of the research proposed here is to exploit the remarkable experimental advantages of the unicellular eukaryote Saccharomyces cerevisiae (yeast) to elucidate general principles and mechanisms of cellular morphogenesis. A feature of cellular morphogenesis in most cells is the development of cell polarity along an appropriate axis, and loss of normal polarity is an early event in the development of epithelial tumors. As yeast chooses nonrandom sites for budding and then polarizes its cytoskeleton and cell-surface growth along the axis defined by the bud site, it provides an attractive model system for investigation of cell polarization. The specific studies proposed here will use a combination of genetic, molecular biological, biochemical, and cell biological methods to investigate two sets of problems. (I) How do persistent spatial markers in the cell cortex and a GTPase signaling module (based on the Ras-like Rsrlp) determine the bipolar pattern of bud-site selection (as normally seen in diploid cells)? (II) How does a second GTPase signalingmodule (based on the Rho-like Cdc42p) control the establishment of cytoskeletal polarization toward the selected bud site? Cytoplasmic division (cytokinesis) is another important aspect of cellular morphogenesis as well as of the cellular reproduction cycle;defects in cytokinesis also appear to contribute to the development of various kinds of cancer. The septins are a novel family of proteins first discovered on the basis of their involvement in cytokinesis in yeast. They are now known to be involved in cytokinesis in insect and mammalian cells as well, and the available evidence suggests that they also have a variety of other roles in the organization of the cell surface. The studies proposed here will use a combination of genetic, molecular biological, biochemical, and cell biological methods to investigate a third set of problems: (III) How do the septins assemble and associate with the plasma membrane? What other proteins do they organize at the cell cortex? What are the roles of the septins both in ordinary cytokinesis and in the specialized process by which spores are formed?
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