OBJECTIVE: Miscarriages affect 10% of women aged 25-29, and 53% of women over 45. The primary cause of miscarriage is aneuploidy that originated in eggs. The Aurora kinase family has three members that regulate chromosome segregation. Therefore, distinguishing the roles of these isoforms is important to understand aneuploidy etiology. In meiosis, Aurora kinase A (AURKA) localizes to spindle poles, where it binds TPX2. Aurora kinase C (AURKC) localizes on chromosomes, where it replaces AURKB as the primary AURK in the chromosomal passenger complex (CPC) via INCENP binding. Although AURKA compensates for CPC function in oocytes lacking AURKB/C, it is unknown whether AURKA binds INCENP in wild type mouse oocytes. ZINC08918027 (ZC) is an inhibitor that prevents the interaction between AURKB and INCENP in mitotic cells. We hypothesized that ZC would block CPC function of any AURK isoform. RESULTS: ZC treatment caused defects in meiotic progression and spindle building. By Western blotting and immunofluorescence, we observed that activated AURKA and AURKC levels in ZC-treated oocytes decreased compared to controls. These results suggest there is a population of AURKA-CPC in mouse oocytes. These data together suggest that INCENP-dependent AURKA and AURKC activities are needed for spindle bipolarity and meiotic progression.

• Klíčová slova
• Aurora kinase, Chromosomal passenger complex, Meiosis, Oocyte,
• MeSH
• aparát dělícího vřeténka metabolismus   MeSH
• aurora kinasa B genetika   metabolismus   MeSH
• meióza * MeSH
• myši MeSH
• oocyty * metabolismus   MeSH
• protein - isoformy genetika   MeSH
• segregace chromozomů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aurora kinasa B MeSH
• protein - isoformy MeSH

The Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile, and their oocytes fail to complete meiosis I. In determining AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at acentriolar microtubule organizing centers (aMTOCs; meiotic spindle poles). This activation induces fragmentation of the aMTOCs, a step essential for building a bipolar spindle. We also show that AURKA is required for regulating localization of TACC3, another protein required for spindle building. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.

• MeSH
• aparát dělícího vřeténka genetika   MeSH
• aurora kinasa A genetika   MeSH
• aurora kinasa B genetika   MeSH
• aurora kinasa C genetika   MeSH
• dělení bunečného jádra genetika   MeSH
• fetální proteiny genetika   MeSH
• lidé MeSH
• meióza genetika   MeSH
• myši MeSH
• oocyty růst a vývoj   metabolismus   MeSH
• organizační centrum mikrotubulů metabolismus   MeSH
• polo-like kinasa 1 MeSH
• póly dělícího vřeténka genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• segregace chromozomů genetika   MeSH
• vývojová regulace genové exprese genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• 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
• Aurkb protein, mouse MeSH Prohlížeč
• Aurkc protein, mouse MeSH Prohlížeč
• aurora kinasa A MeSH
• aurora kinasa B MeSH
• aurora kinasa C MeSH
• fetální proteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny asociované s mikrotubuly MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny MeSH
• TACC3 protein, mouse MeSH Prohlížeč

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