Systems biology of size control in eukaryotes

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In addition to be the fundamental unit of life, the cell is also the basic unit of growth. Understanding what regulates the overall growth of cell and how this is coordinated with progression of the cell cycle are longstanding problems in cell biology. During the last century, a major focus of cell biology has been the study of cell division, but how eukaryotic cells couple growth to division to maintain a homeostatic size remains poorly understood. Cell size of a microorganism is influenced by the quality and the quantity of nutrients in the surrounding environment. For instance, yeast cells growing in the presence of their optimal carbon source, glucose, are larger than cells growing in ethanol or glycerol as a sole source of carbon. This emphasizes an intimate link between the machinery that sense the nutritional status of the environment and the mechanism that coordinate growth and division and consequently cell size. Many studies have shown that transcriptional networks and signaling pathways have been subjected to numerous evolutionary changes in the budding yeast Saccharomyces cerevisiae as compared to other species. Thus, despite its preeminent role as a genetically tractable model system, insights gained into cell size control mechanisms in S. cerevisiae may not be generalizable. Indeed, our systematic screen for size mutants in the opportunistic yeast Candida albicans revealed a divergence of central regulators, such as the MAPK module HOG/p38, consistent with an evolutionary plasticity of the size control network. The goal of this research program is to understand how Hog1 modulates cell size and what are the upstream signals sensed by this pathway to preserve size homeostasis (AIM #1). Interestingly, we have shown that the role of some of those size genes such as the Hog1/p38s were also conserved in humans. Thus, we will test the hypothesis that other conserved genes that affect size in C. albicans may also modulate size in human cells (AIM #2). A central question in size control is how the size threshold adapts to environmental variation. It has been argued that optimization of organism size is a dominant evolutionary force because fitness depends exquisitely on adaptation to a particular size niche. The strong link between size and fitness has been elegantly demonstrated through the artificial evolution of E. coli strains adapted to different growth rates. Here, we seek to delineate the nutrient-dependent size control machinery in C. albicans. We expect that this study will provide fundamental insights into mechanisms of eukaryotic cell cycle commitment (AIM #3). The proposed studies will generate extensive datasets and hypothesis suitable for HQP training and for further in-depth investigations supported by a variety of other competitive funding agencies.