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Updated: May 23, 2026
Evaluation of the Spindle Assembly Checkpoint Integrity in Mouse Oocytes
Published on: September 13, 2022
Spindle assembly checkpoint signalling is uncoupled from chromosomal position in mouse oocytes
1Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Abstract:
The spindle assembly checkpoint (SAC) averts aneuploidy by coordinating proper bipolar chromosomal attachment with anaphase-promoting complex/cyclosome (APC/C)-mediated securin and cyclin B1 destruction required for anaphase onset. The generation of a Mad2-based signal at kinetochores is central to current models of SAC-based APC/C inhibition. During mitosis, kinetochores of polar-displaced chromosomes, which are at greatest risk of mis-segregating, recruit the highest levels of Mad2, thereby ensuring that SAC activation is proportionate to aneuploidy risk. Paradoxically, although an SAC operates in mammalian oocytes, meiosis I (MI) is notoriously error prone and polar-displaced chromosomes do not prevent anaphase onset. Here we find that Mad2 is not preferentially recruited to the kinetochores of polar chromosomes of wild-type mouse oocytes, in which polar chromosomes are rare, or of oocytes depleted of the kinesin-7 motor CENP-E, in which polar chromosomes are more abundant. Furthermore, in CENP-E-depleted oocytes, although polar chromosomal displacement intensified during MI and the capacity to form stable end-on attachments was severely compromised, all kinetochores nevertheless became devoid of Mad2. Thus, it is possible that the ability of the SAC to robustly discriminate chromosomal position might be compromised by the propensity of oocyte kinetochores to become saturated with unproductive attachments, thereby predisposing to aneuploidy. Our data also reveal novel functions for CENP-E in oocytes: first, CENP-E stabilises BubR1, thereby impacting MI progression; and second, CENP-E mediates bi-orientation by promoting kinetochore reorientation and preventing chromosomal drift towards the poles.
Insights
Mammalian oocytes exhibit a compromised spindle assembly checkpoint (SAC), leading to aneuploidy. Unlike mitosis, SAC fails to prevent anaphase onset in oocytes, even with misaligned chromosomes, due to issues with Mad2 recruitment and kinetochore attachments.
Area of Science:
- Cell Biology
- Genetics
- Reproductive Biology
Background:
- The spindle assembly checkpoint (SAC) is crucial for preventing aneuploidy by ensuring proper chromosome attachment before anaphase onset.
- Current models propose Mad2-dependent signaling at kinetochores is central to SAC-mediated inhibition of the anaphase-promoting complex/cyclosome (APC/C).
- In mitosis, SAC activation is proportional to aneuploidy risk, with higher Mad2 recruitment to kinetochores of polar-displaced chromosomes.
Purpose of the Study:
- To investigate why mammalian oocytes, despite possessing an SAC, are prone to errors during meiosis I (MI) and aneuploidy.
- To examine Mad2 recruitment to kinetochores of polar chromosomes in wild-type and CENP-E-depleted mouse oocytes.
- To elucidate novel functions of CENP-E in oocyte meiosis.
Main Methods:
- Analysis of Mad2 recruitment to kinetochores in wild-type and CENP-E-depleted mouse oocytes during meiosis I.
- Microscopy to assess chromosomal displacement and kinetochore attachments.
- Investigation of CENP-E's role in stabilizing BubR1 and mediating chromosome bi-orientation.
Main Results:
- Mad2 was not preferentially recruited to polar chromosomes in either wild-type or CENP-E-depleted oocytes.
- In CENP-E-depleted oocytes, despite increased polar chromosomal displacement and compromised attachments, kinetochores became devoid of Mad2.
- CENP-E was found to stabilize BubR1 and mediate kinetochore reorientation, preventing chromosomal drift.
Conclusions:
- The SAC's ability to discriminate chromosomal position may be impaired in oocytes due to kinetochore saturation with unproductive attachments, leading to aneuploidy.
- CENP-E plays critical roles in oocyte meiosis, including stabilizing BubR1 for MI progression and ensuring proper chromosome bi-orientation.
- These findings highlight potential mechanisms underlying oocyte aneuploidy and the specific functions of CENP-E in this context.
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