Aurora kinase A is essential for meiosis in mouse oocytes

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.

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Aurora kinase A is essential for meiosis in mouse oocytes

10.1101/2021.01.08.425851 ◽

2021 ◽

Author(s):

Cecilia S. Blengini ◽

Patricia Ibrahimian ◽

Michaela Vaskovicova ◽

David Drutovic ◽

Petr Solc ◽

...

Keyword(s):

Chromosome Segregation ◽

Aurora Kinase ◽

The Other ◽

Meiotic Spindle ◽

Independent Manner ◽

Aurora Kinase A ◽

Mouse Oocytes ◽

Spindle Poles ◽

Knockout Model ◽

Kinase A

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 the AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at microtubule organizing centers (MTOCs; meiotic spindle poles). This activation induces fragmentation of the MTOCs, a step essential for building a bipolar spindle. The next step that requires AURKA is building the liquid-like spindle domain that involves TACC3. Finally, we find that AURKA is also required for anaphase I onset to trigger cohesin cleavage in an APC/C independent manner. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.

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CEP215 and AURKA regulate spindle pole focusing and aMTOC organization in mouse oocytes

Reproduction ◽

10.1530/rep-19-0263 ◽

2020 ◽

Vol 159 (3) ◽

pp. 261-274

Author(s):

Xiaotian Wang ◽

Claudia Baumann ◽

Rabindranath De La Fuente ◽

Maria M Viveiros

Keyword(s):

Critical Role ◽

Super Resolution ◽

Aurora Kinase ◽

Spindle Pole ◽

Meiotic Spindle ◽

Dependent Manner ◽

Aurora Kinase A ◽

Mouse Oocytes ◽

Kinase A

Acentriolar microtubule-organizing centers (aMTOCs) play a critical role in stable meiotic spindle assembly in oocytes, necessary for accurate chromosome segregation. Yet, there is a limited understanding of the essential regulatory components of these unique MTOCs. In somatic cells, CEP215 (Centrosomal Protein 215) serves as an important regulator of centrosome maturation and spindle organization. Here, we assessed whether it has a similar function in mouse oocytes. CEP215 was detected in oocyte lysates and specifically localized to aMTOCs throughout the progression of meiosis in a pericentrin-dependent manner. Super-resolution microscopy revealed CEP215 co-localization with pericentrin and a unique pore/ring-like structural organization of aMTOCs. Interestingly, inhibition of Aurora Kinase A in either MI or MII-stage oocytes resulted in a striking loss of the ring-like aMTOC organization and pronounced CEP215 clustering at spindle poles, as well as shorter spindles with highly focused poles. In vitro siRNA-mediated transcript knockdown effectively reduced CEP215 in approximately 85% of the oocytes. Maturation rates to MII were similar in the Cep215 siRNA and injected controls; however, a high percentage (~40%) of the Cep215-knockdown oocytes showed notable variations in spindle pole focusing. Surprisingly, pericentrin and γ-tubulin localization and fluorescence intensity at aMTOCs were unaltered in knockdown oocytes, contrasting with mitotic cells where CEP215 depletion reduced γ-tubulin at centrosomes. Our results demonstrate that CEP215 is a functional component of oocyte aMTOCs and participates in the regulation of meiotic spindle pole focusing. Moreover, these studies reveal a vital role for Aurora Kinase A activity in the maintenance of aMTOC organization in oocytes.

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

Biology of Reproduction ◽

10.1095/biolreprod.112.101014 ◽

2012 ◽

Vol 87 (4) ◽

Cited By ~ 22

Author(s):

Petr Solc ◽

Vladimir Baran ◽

Alexandra Mayer ◽

Tereza Bohmova ◽

Gabriela Panenkova-Havlova ◽

...

Keyword(s):

Aurora Kinase ◽

Aurora Kinase A ◽

Mouse Oocytes ◽

Kinase A

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Aurora kinase A controls meiosis I progression in mouse oocytes

Cell Cycle ◽

10.4161/cc.6361 ◽

2008 ◽

Vol 7 (15) ◽

pp. 2368-2376 ◽

Cited By ~ 56

Author(s):

Adela Saskova ◽

Petr Solc ◽

Vladimir Baran ◽

Michal Kubelka ◽

Richard M. Schultz ◽

...

Keyword(s):

Aurora Kinase ◽

Aurora Kinase A ◽

Mouse Oocytes ◽

Kinase A ◽

Meiosis I

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Mechanisms underlying disruption of oocyte spindle stability by bisphenol compounds

Reproduction ◽

10.1530/rep-19-0494 ◽

2020 ◽

Vol 159 (4) ◽

pp. 383-396 ◽

Cited By ~ 1

Author(s):

Luhan Yang ◽

Claudia Baumann ◽

Rabindranth De La Fuente ◽

Maria M Viveiros

Keyword(s):

Aurora Kinase ◽

Rapid Onset ◽

Spindle Pole ◽

Potential Interaction ◽

Meiotic Spindle ◽

Dependent Manner ◽

Aurora Kinase A ◽

Multipolar Spindles ◽

Spindle Stability ◽

Kinase A

Accurate chromosome segregation relies on correct chromosome-microtubule interactions within a stable bipolar spindle apparatus. Thus, exposure to spindle disrupting compounds can impair meiotic division and genomic stability in oocytes. The endocrine disrupting activity of bisphenols such as bisphenol A (BPA) is well recognized, yet their damaging effects on spindle microtubules (MTs) is poorly understood. Here, we tested the effect(s) of acute exposure to BPA and bisphenol F (BPF) on assembled spindle stability in ovulated oocytes. Brief (4 h) exposure to increasing concentrations (5, 25, and 50 µg/mL) of BPA or BPF disrupted spindle organization in a dose-dependent manner, resulting in significantly shorter spindles with highly unfocused poles and fragmented pericentrin. The chromosomes remained congressed in an abnormally elongated metaphase-like configuration, yet normal end-on chromosome-MT attachments were reduced in BPF-treated oocytes. Live-cell imaging revealed a rapid onset of bisphenol-mediated spindle MT disruption that was reversed upon compound removal. Moreover, MT stability and regrowth were impaired in BPA-exposed oocytes, with few cold-stable MTs and formation of multipolar spindles upon MT regrowth. MT-associated kinesin-14 motor protein (HSET/KIFC1) labeling along the spindle was also lower in BPA-treated oocytes. Conversely, cold stable MTs and HSET labeling persisted after BPF exposure. Notably, inhibition of Aurora Kinase A limited bisphenol-mediated spindle pole widening, revealing a potential interaction. These results demonstrate rapid MT disrupting activity by bisphenols, which is highly detrimental to meiotic spindle stability and organization. Moreover, we identify an important link between these defects and altered distribution of key spindle associated factors as well as Aurora Kinase A activity.

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