Maternally recruited Aurora C kinase is more stable than Aurora B to support mouse oocyte maturation and early development

Abstract

Aurora kinases are highly conserved, essential regulators of cell division. Two Aurora kinase isoforms, A and B (AURKA and AURKB), are expressed ubiquitously in mammals, whereas a third isoform, Aurora C (AURKC), is largely restricted to germ cells. Because AURKC is very similar to AURKB, based on sequence and functional analyses, why germ cells express AURKC is unclear. We report that Aurkc −/− females are subfertile, and that AURKB function declines as development progresses based on increasing severity of cytokinesis failure and arrested embryonic development. Furthermore, we find that neither Aurkb nor Aurkc is expressed after the one-cell stage, and that AURKC is more stable during maturation than AURKB using fluorescently tagged reporter proteins. In addition, Aurkc mRNA is recruited during maturation. Because maturation occurs in the absence of transcription, posttranscriptional regulation of Aurkc mRNA, coupled with the greater stability of AURKC protein, provides a means to ensure sufficient Aurora kinase activity, despite loss of AURKB, to support both meiotic and early embryonic cell divisions. These findings suggest a model for the presence of AURKC in oocytes: that AURKC compensates for loss of AURKB through differences in both message recruitment and protein stability.A urora kinases are highly conserved cell-cycle regulators with essential roles in chromosome segregation. There are three Aurora kinases in mammals: Aurora kinases A and B (AURKA or -B) are ubiquitously expressed and their functions have been extensively studied, whereas AURKC is largely limited to germ cells (1-3); many human cancer cell lines express AURKC (4) and some somatic tissues express AURKC at low levels (5-7). It is not clear, however, why germ cells require a third AURK. Because isoforms can have different functions, it is tempting to speculate that AURKC exists because its mitotic counterparts simply cannot execute unique features of meiosis.One unique feature of meiosis is the generation of haploid gametes from diploid precursor cells by a reductional chromosome segregation during meiosis I (MI) followed by an equational division at meiosis II (MII) without an intervening round of DNA replication. In oocytes, another unique feature is that meiosis is not a continuous process because there is a growth period during a prolonged arrest at prophase I, followed by a cell division cycle during oocyte maturation, and a second arrest at metaphase of MII, until fertilization, which triggers completion of MII. Furthermore, proteins in the oocyte must support the first mitotic cell cycles of the embryo before zygotic genome activation. Despite these obvious differences, several observations suggest that AURKC may not have a specialized function. AURKB and AURKC are highly similar in sequence (61% identical), and AURKC can functionally compensate for loss of AURKB when ectopically expressed in somatic cells (8, 9). Furthermore, embryos that lack AURKB can develop to but not beyond the blastocyst, as long as AURKC is present, consis...

Inherent Instability of Correct Kinetochore-Microtubule Attachments during Meiosis I in Oocytes

“…In mouse oocytes, Aurora C, which has a sequence and functions similar to those of Aurora B (Li et al, 2004;Sasai et al, 2004), is stably expressed (Schindler et al, 2012;Tseng et al, 1998) and plays a role as a predominant kinase of the chromosome passenger complex (Balboula and Schindler, 2014). Aurora B and C (B/C) are known to destabilize incorrect KT-MT attachments in mouse oocytes (Balboula and Schindler, 2014;Davydenko et al, 2013;Rattani et al, 2013;Yang et al, 2010).…”

Reduced Chromosome Cohesion Measured by Interkinetochore Distance Is Associated with Aneuploidy Even in Oocytes from Young Mice1

“…Its ability to do this may be due to inhibition of Aurora kinase B, which is normally involved in the destabilization of erroneous microtubulekinetochore interactions during prometaphase [19,20]. Oocytes also contain the gamete-specific Aurora kinase C that may also contribute to this error correction pathway and would be predicted to be similarly inhibited by this drug [21]. Persistence of such errors at anaphase onset would consequently lead to chromosome missegregation.…”

Aurora Kinase A Drives MTOC Biogenesis but Does Not Trigger Resumption of Meiosis in Mouse Oocytes Matured In Vivo1

“…Although securin is destroyed in anaphase and homologous chromosomes separate in meiosis I following overexpression of AURKC, overexpression of AURKB blocks proper anaphase-promoting complex/cyclosome activation and securin destruction [28]. The results of recent experiments find that female mice lacking AURKC are subfertile partly as a result of chromosome misalignment that leads to MI arrest and that AURKB protein is less stable than AURKC during meiotic maturation [29].…”