Errors in chromosome segregation during female meiosis I occur frequently, and aneuploid embryos account for 1/3 of all miscarriages in humans [1]. Unlike mitotic cells that require two Aurora kinase (AURK) homologs to help prevent aneuploidy (AURKA and AURKB), mammalian germ cells also require a third (AURKC) [2, 3]. AURKA is the spindle-pole-associated homolog, and AURKB/C are the chromosome-localized homologs. In mitosis, AURKB has essential roles as the catalytic subunit of the chromosomal passenger complex (CPC), regulating chromosome alignment, kinetochore-microtubule attachments, cohesion, the spindle assembly checkpoint, and cytokinesis [4, 5]. In mouse oocyte meiosis, AURKC takes over as the predominant CPC kinase [6], although the requirement for AURKB remains elusive [7]. In the absence of AURKC, AURKB compensates, making defining potential non-overlapping functions difficult [6, 8]. To investigate the role(s) of AURKB and AURKC in oocytes, we analyzed oocyte-specific Aurkb and Aurkc single- and double-knockout (KO) mice. Surprisingly, we find that double KO female mice are fertile. We demonstrate that, in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner. These data suggest that AURKC prevents AURKA from localizing to chromosomes by competing for CPC binding. This competition is important for adequate spindle length to support meiosis I. We also describe a unique requirement for AURKB to negatively regulate AURKC to prevent aneuploidy. Together, our work reveals oocyte-specific roles for the AURKs in regulating each other's localization and activity. This inter-kinase regulation is critical to support wild-type levels of fecundity in female mice.
- Klíčová slova
- Aurora kinase, aneuploidy, fertility, meiosis, meiotic maturation, oocyte,
- MeSH
- aneuploidie MeSH
- aurora kinasa A genetika metabolismus MeSH
- aurora kinasa B genetika metabolismus MeSH
- aurora kinasa C genetika metabolismus MeSH
- fertilita genetika MeSH
- meióza * MeSH
- myši MeSH
- oocyty metabolismus MeSH
- segregace chromozomů genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- Aurka protein, mouse MeSH Prohlížeč
- Aurkb protein, mouse MeSH Prohlížeč
- Aurkc protein, mouse MeSH Prohlížeč
- aurora kinasa A MeSH
- aurora kinasa B MeSH
- aurora kinasa C MeSH
Meiotic oocytes lack classic centrosomes and, therefore, bipolar spindle assembly depends on clustering of acentriolar microtubule-organizing centers (MTOCs) into two poles. However, the molecular mechanism regulating MTOC assembly into two poles is not fully understood. The kinase haspin (also known as GSG2) is required to regulate Aurora kinase C (AURKC) localization at chromosomes during meiosis I. Here, we show that inhibition of haspin perturbed MTOC clustering into two poles and the stability of the clustered MTOCs. Furthermore, we show that AURKC localizes to MTOCs in mouse oocytes. Inhibition of haspin perturbed the localization of AURKC at MTOCs, and overexpression of AURKC rescued the MTOC-clustering defects in haspin-inhibited oocytes. Taken together, our data uncover a role for haspin as a regulator of bipolar spindle assembly by regulating AURKC function at acentriolar MTOCs in oocytes.
- Klíčová slova
- Aurora kinase, Haspin, MTOC, Oocyte, Spindle,
- MeSH
- aparát dělícího vřeténka metabolismus MeSH
- aurora kinasa C metabolismus MeSH
- intracelulární signální peptidy a proteiny antagonisté a inhibitory metabolismus MeSH
- metafáze MeSH
- myši MeSH
- oocyty metabolismus MeSH
- organizační centrum mikrotubulů metabolismus MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory metabolismus MeSH
- transport proteinů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aurora kinasa C MeSH
- Haspin protein, mouse MeSH Prohlížeč
- intracelulární signální peptidy a proteiny MeSH
- protein-serin-threoninkinasy MeSH