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Molecular and Cellular Biology, February 2009, p. 1059-1071, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01062-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Aurora-A Kinase Is Essential for Bipolar Spindle Formation and Early Development{triangledown} ,{dagger}

Dale O. Cowley,1,{ddagger} Jaime A. Rivera-Pérez,2,§ Mark Schliekelman,3 Yizhou Joseph He,3 Trudy G. Oliver,1,¶ Lucy Lu,1 Ryan O'Quinn,4 E. D. Salmon,4 Terry Magnuson,2 and Terry Van Dyke1*

Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599,1 Department of Genetics and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599-7264,2 Curriculum in Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,3 Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275994

Received 8 July 2008/ Returned for modification 1 August 2008/ Accepted 27 November 2008

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.

* Corresponding author. Mailing address: School of Medicine, CB7299, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 962-2145. Fax: (919) 843-3160. E-mail: tvdlab{at}med.unc.edu

{triangledown} Published ahead of print on 15 December 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: GlaxoSmithKline, Research Triangle Park, NC 27509.

§ Present address: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655.

Present address: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02142.

Molecular and Cellular Biology, February 2009, p. 1059-1071, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.01062-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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