Regulation of mitosis and morphogenesis in the fungal pathogen Candida albicans

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My research focuses on the regulation of eukaryotic cell cycle progression and morphogenesis. Defects in these processes have crucial implications for cell proliferation, development, and cancer. We are specifically investigating the regulation of mitosis and morphogenesis in Candida albicans, an important fungal pathogen of humans. C. albicans can switch between yeast, pseudohyphae, and polarized hyphal cells. This behavior is critical for pathogenesis; cells locked in one form loose virulence. The yeast-to-hyphal switch is regulated by environmental cues, but the mechanisms are not fully understood. Regulation of the cell cycle and cell proliferation in C. albicans is even less clear. Our work on mitotic regulators in C. albicans, including the polo-like kinase Cdc5p, and activators of the Anaphase Promoting Complex/ Cyclosome, revealed distinct features compared to other fungi that suggest re-wiring in the mitotic circuitry. We also demonstrated that cell cycle signals profoundly influence morphogenesis. Mitotic arrest in yeast resulted in highly polarized cells that were distinct from true hyphae in may respects, yet expressed several hyphal virulence genes at later growth stages. In contrast, mitotic arrest through similar means prevents cell proliferation in other systems. Thus, C. albicans shows a novel relationship between mitotic progression and morphogenesis, but the mechanisms controlling mitosis, associated polar growth and expression of virulence genes normally under control of environmental signaling pathways remain unclear. Genetic and biochemical screens coupled with molecular approaches and live cell imaging will be utilized to 1) define the mechanisms of action of mitotic regulators in C. albicans, in order to gain insights on the control of cell proliferation; and 2) determine the mechanisms underlying the distinct relationship between mitosis, polarized growth and activation of virulence genes, in order to uncover novel circuitry linking these processes. Our work will have novel implications for the control of cell proliferation, morphogenesis, and virulence in an important pathogen, the diversity in eukaryotic cell cycle networks, and the interplay between the cell cycle and development.