Aurora-A kinase is essential for bipolar spindle formation and early development
Department of Cell Biology
Medical Subject Headings
Alleles; Animals; Apoptosis; Blastocyst; Cell Proliferation; Embryo Loss; Embryo, Mammalian; *Embryonic Development; Female; Fibroblasts; Gene Deletion; Gene Targeting; Mice; Mitosis; Mitotic Spindle Apparatus; Mutation; Ploidies; Pregnancy; Protein-Serine-Threonine Kinases
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.
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Citation: Mol Cell Biol. 2009 Feb;29(4):1059-71. Epub 2008 Dec 15. Link to article on publisher's site