The role of centrosomes in cell proliferation, division, and development

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Centrioles organize centrosomes by recruiting pericentriolar material that nucleates and anchors microtubules. Centrosomes, in turn, direct the assembly of focal microtubule arrays in cells. Although discovered over 100 years ago, the contribution of centrosomes to cell proliferation, cell division, and development remains an important topic of current research. My sponsor lab recently developed an inhibitor of the kinase Plk4, which controls new centriole formation. Treatment of cells with this inhibitor, called centrinone, allows depletion of centrosomes from vertebrate cells. My project aims to use centrinone as a tool to shed light on the role of centrosomes in cell proliferation, division and development. Work in my sponsor lab has shown that normal cells possess a p53 dependent sensor that detects centrosome loss and arrests cells in G1, whereas transformed cells lacking an intact p53 pathway continue to proliferate. The goal of the first aim of this proposal is to understand the molecular mechanisms underlying the ability of cells to sense centrosome loss. Therefore, I will take utilize a functional approach based on our current understanding of centrosome structure and composition to understand how centrosome loss leads to p53 activation. The second aim builds on my preliminary finding that centrosome removal does not apparently alter the structure of the astral microtubule arrays in anaphase cells. Here I would like to understand how astral microtubule arrays form when centrosomes are absent and to use this information to study the role of astral microtubules in patterning the cortical accumulation of contractile ring proteins during cytokinesis. In the third aim, I will use human embryonic stem cells as a model to analyze the role of centrosomes and astral microtubules in spindle orientation during development. In particular, I plan to determine how centrosomes and the NuMA/LGN/Gai pathway contribute to Wnt-mediated spindle orientation. In summary, the proposed work will capitalize on the availability of centrinone as a tool to investigate the role of centrosomes in competence for proliferation, defining the division plane, and in polarized cell divisions during development.