title: Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality.
abstract: Aurora A (also known as STK15/BTAK in humans), a putative oncoprotein naturally overexpressed in many human cancers, is a member of the conserved Aurora protein serine/threonine kinase family that is implicated in the regulation of G(2)-M phases of the cell cycle. In vitro studies utilizing antibody microinjection, siRNA silencing and small molecule inhibitors have indicated that Aurora A functions in early as well as late stages of mitosis. However, due to limitations in specificity of the techniques, exact functional roles of the kinase remain to be clearly elucidated. In order to identify the physiological functions in vivo, we have generated Aurora A null mouse embryos, which show severe defects at 3.5 d.p.c. (days post-coitus) morula/blastocyst stage and lethality before 8.5 d.p.c. Null embryos at 3.5 d.p.c. reveal growth retardation with cells in mitotic disarray manifesting disorganized spindle, misaligned and lagging chromosomes as well as micronucleated cells. These findings provide the first unequivocal genetic evidence for an essential physiological role of Aurora A in normal mitotic spindle assembly, chromosome alignment segregation and maintenance of viability in mammalian embryos.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sasai
authors.forename: J M
authors.initials: JM
authors.lastname: Parant
authors.forename: M E
authors.initials: ME
authors.lastname: Brandt
authors.forename: J
authors.initials: J
authors.lastname: Carter
authors.forename: H P
authors.initials: HP
authors.lastname: Adams
authors.forename: S A
authors.initials: SA
authors.lastname: Stass
authors.forename: A M
authors.initials: AM
authors.lastname: Killary
authors.forename: H
authors.initials: H
authors.lastname: Katayama
authors.forename: S
authors.initials: S
authors.lastname: Sen
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss / Q000201:enzymology* / Q000235:genetics; D004622:Embryo, Mammalian / Q000201:enzymology*; D016195:G2 Phase / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D009028:Morula / Q000201:enzymology / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases