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Abstract
Aurora-A is a conserved kinase implicated in mitotic regulation and carcinogenesis. Aurora-A was previously implicated in mitotic entry and spindle assembly, although contradictory results prevented a clear understanding of the roles of Aurora-A in mammals. We developed a conditional null mutation in the mouse Aurora-A gene to investigate Aurora-A functions in primary cells ex vivo and in vivo. We show here that conditional Aurora-A ablation in cultured embryonic fibroblasts causes impaired mitotic entry and mitotic arrest with a profound defect in bipolar spindle formation. Germ line Aurora-A deficiency causes embryonic death at the blastocyst stage with pronounced cell proliferation failure, mitotic arrest, and monopolar spindle formation. Aurora-A deletion in mid-gestation embryos causes an increase in mitotic and apoptotic cells. These results indicate that murine Aurora-A facilitates, but is not absolutely required for, mitotic entry in murine embryonic fibroblasts and is essential for centrosome separation and bipolar spindle formation in vitro and in vivo. Aurora-A deletion increases apoptosis, suggesting that molecular therapies targeting Aurora-A may be effective in inducing tumor cell apoptosis. Aurora-A conditional mutant mice provide a valuable system for further defining Aurora-A functions and for predicting effects of Aurora-A therapeutic intervention.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank members of the Van Dyke, Magnuson, and Salmon laboratories for helpful discussions and technical assistance. We acknowledge the use of Michael Hooker Microscopy Core Facility equipment and resources funded by an anonymous private donor and Sundeep Kalantry, Michael Chua, and Wendy Salmon for expert assistance with confocal microscopy. We thank Allan Balmain for critical reading and comments on the manuscript.
D.O.C. was a fellow of the Leukemia & Lymphoma Foundation of America (grant 5408-02). This study was supported by NCI grant 2-R01-CA065773-11A1 to T.V.D., NIH grant GM24364 to E.D.S., and an NICHD grant to T.M.