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

Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2012; 109(33):E2215-22. DOI: 10.1073/pnas.1120517109
Source: PubMed


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.

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    • "Evidence of these differences can be seen in the divergent phenotypes of knockout mice. Aurkb −/− die at the blastocyst embryonic stage while Aurkc −/− knockouts are viable (Kimmins et al., 2007; Schindler et al., 2012). Transgenic mice expressing a dominant negative AURKB driven by the male-specific β-4-galactosyltransferase promoter exhibit severe disruption in spermatogenesis with reduced sperm counts, reduced testis size and disorganized spermatogenic staging. "
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    ABSTRACT: The mammalian genome encodes three Aurora kinase protein family members: A, B, and C. While Aurora kinase A (AURKA) and B (AURKB) are found in cells throughout the body, significant protein levels of Aurora kinase C (AURKC) are limited to cells that undergo meiosis (sperm and oocyte). Despite its discovery nearly 20 years ago, we know little about the function of AURKC compared to that of the other 2 Aurora kinases. This lack of understanding can be attributed to the high sequence homology between AURKB and AURKC preventing the use of standard approaches to understand non-overlapping and meiosis I (MI)-specific functions of the two kinases. Recent evidence has revealed distinct functions of AURKC in meiosis and may aid in our understanding of why chromosome segregation during MI often goes awry in oocytes. Many cancers aberrantly express AURKC, but because we do not fully understand AURKC function in its normal cellular context, it is difficult to predict the biological significance of this expression on the disease. Here, we consolidate and update what is known about AURKC signaling in meiotic cells to better understand why it has oncogenic potential.
    Frontiers in Cell and Developmental Biology 09/2015; 3:50. DOI:10.3389/fcell.2015.00050
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    • "), and its function is important for meiotic cell cycle progression (Hu et al., 2000; Chen et al., 2005; Tang et al., 2006; Yang et al., 2010; Schindler et al., 2012; Yang et al., 2013; Balboula and Schindler, 2014) and post-meiotic sperm development (Kimmins et al., 2007). However, the expression levels in single oocytes relative to other cell types and the expression of the individual splice variants is not known. "
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    ABSTRACT: Chromosome segregation is an extensively choreographed process yet errors still occur frequently in female meiosis, leading to implantation failure, miscarriage or offspring with developmental disorders. Aurora kinase C (AURKC) is a component of the chromosome passenger complex and is highly expressed in gametes. Studies in mouse oocytes indicate that AURKC is required to regulate chromosome segregation during meiosis I (MI); however, little is known about the functional significance of AURKC in human oocytes. Three splice variants of AURKC exist in testis tissue. To determine which splice variants human oocytes express, we performed quantitative real time PCR using single oocytes and found expression of all three variants. To evaluate the functional differences between the variants, we created GFP-tagged constructs of each variant to express in oocytes from Aurkc(-/-) mice. By quantifying metaphase chromosome alignment, cell cycle progression, phosphorylation of INCENP, and microtubule attachments to kinetochores, we found that AURKC_v1 was the most capable of the variants at supporting metaphase I chromosome segregation. AURKC_v3 localized to chromosomes properly and supported cell cycle progression to metaphase II, but its inability to correct erroneous microtubule attachments to kinetochores meant that chromosome segregation was not as accurate compared to that caused by the other three variants. Finally when we expressed the three variants simultaneously, error correction was more robust than when they were expressed on their own. Therefore, oocytes express three variants of AURKC that are not functionally equivalent in supporting meiosis, but fully complement meiosis when expressed simultaneously. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Molecular Human Reproduction 05/2015; 21(8). DOI:10.1093/molehr/gav026 · 3.75 Impact Factor
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    • "Journal of Cell Science (2014) 127, 5066–5078 doi:10.1242/jcs.158840 non-overlapping functions from AURKB in wild-type oocytes (Balboula and Schindler, 2014; Schindler et al., 2012). These functions include regulating the correction of improper kinetochore–microtubule attachments to ensure correct chromosome alignment and segregation during MI (Balboula and Schindler, 2014). "
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    ABSTRACT: Meiosis I (MI), the division that generates haploids, is prone to errors that lead to aneuploidy in females. Haspin is a kinase that phosphorylates histone H3 on threonine 3, thereby recruiting Aurora kinase B (AURKB) and the chromosomal passenger complex (CPC) to kinetochores to regulate mitosis. Haspin and AURKC, an AURKB homolog, are enriched in germ cells, yet their significance in regulating MI is not fully understood. Using inhibitors and overexpression approaches, we show a role for haspin during MI in mouse oocytes. Haspin-perturbed oocytes display abnormalities in chromosome morphology and alignment, improper kinetochore-microtubule attachments at metaphase I and aneuploidy at metaphase II. Unlike in mitosis, kinetochore localization remained intact, whereas the distribution of the CPC along chromosomes was absent. The meiotic defects following haspin inhibition were similar to those observed in oocytes where AURKC was inhibited, suggesting that the correction of microtubule attachments during MI requires AURKC along chromosome arms rather than at kinetochores. Our data implicate haspin as a regulator of the CPC and chromosome segregation during MI, while highlighting important differences in how chromosome segregation is regulated between MI and mitosis.
    Journal of Cell Science 12/2014; 27(23):5066-78.. DOI:10.1242/jcs.158840 · 5.43 Impact Factor
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