Spindle assembly checkpoint signalling is uncoupled from chromosomal position in mouse oocytes

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.