Aurora-A kinase is essential for bipolar spindle formation and early development.
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.
Cowley
Dale O
DO
Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 275991, USA.
Rivera-Pérez
Jaime A
JA
Schliekelman
Mark
M
He
Yizhou Joseph
YJ
Oliver
Trudy G
TG
Lu
Lucy
L
O'Quinn
Ryan
R
Salmon
E D
ED
Magnuson
Terry
T
Van Dyke
Terry
T
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001755:Blastocyst / Q000166:cytology / Q000201:enzymology; D049109:Cell Proliferation; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D047108:Embryonic Development; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D017353:Gene Deletion; D018390:Gene Targeting; D051379:Mice; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D011003:Ploidies; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D008941:Spindle Apparatus / Q000201:enzymology*
C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases