Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Abstract

SUMMARYMitosis is controlled by multiple kinases that drive cell cycle progression and prevent chromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form the chromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in early lethality at the morula stage, we show here that aurora B is dispensable for CPC function during early cell divisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora C during these early embryonic cycles. Expression of aurora C decreases during late blastocyst stages resulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundant prometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditional deletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignment and lack of chromosome segregation. Re-expression of wild-type, but not kinase-dead, aurora C rescues this defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partially arrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assembly checkpoint.

Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development

“…1a). We were not able to obtain homozygous Aurkb lox-tet/lox-tet or Aurkb tet/tet mutants from crosses between heterozygous mice, in agreement with a lethal phenotype caused by the lack of Aurora B in embryos (34).…”

“…Reducing Aurora B activity by means of RNA interference or small-molecule inhibitors results in failure in chromosome alignment and defective kinetochore-microtubule attachment, cleavage furrow formation, and cytokinesis, ultimately leading to tetraploidization (36)(37)(38)(39). Aurora B heterozygosity in the mouse results in increased tumor incidence, whereas complete loss of Aurkb prevents chromosome segregation and results in a premature mitotic exit (26,34).…”

Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice

“…To examine this idea further, we measured for changes, with respect to maternal age, in levels of 2 proteins: Mad2 and phosphorylated Aurora C (pAurora C). Aurora C is a substitute of Aurora B during meiosis, [34][35][36][37] and its active form pAurora C is thought to be involved in destabilizing erroneous KT-MT attachment, as such contributing to the fidelity of bivalent division. 34,[38][39][40] One further reason for examining Mad2 is that previous studies have shown that levels of this transcript, like those of other SAC components, are lower in oocytes of both aged mice and humans.…”

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

“…Aurora-B or Aurora-C. On the other hand, given that Aurora-B and Aurora-C participate in the same CPC complex and are thought to play similar roles in mitosis (Fernández-Miranda et al 2011), their simultaneous inhibition has the advantage of preventing possible functional compensations. Inactivation of Aurora-A has been reported to induce the formation of either monopolar or multipolar spindles with microtubules of decreased mass and aberrant morphology, unable to align the condensed chromosomes on the metaphasic plate correctly.…”