New evidence that SAC can tolerate misaligned chromosomes in mouse oocytes

Abstract

Comment on: Sebestova J, et al. Cell Cycle 2012; 11:3011-8.

Keywords: :

• meiosis
• chromosome segregation
• spindle assembly checkpoint
• oocyte
• aging
• live-cell imaging

This article refers to:

Lack of response to unaligned chromosomes in mammalian female gametes

Spindle assembly checkpoint (SAC) is a biochemical pathway that monitors the attachment state of kinetochores and delays anaphase onset until all kinetochores are attached to spindle microtubules (Fig. 1).¹ Thus, SAC is crucial for proper segregation of chromosomes during both mitosis and meiosis. However, it is well established that chromosome segregation in female meiosis I is error-prone and is the major cause of miscarriages, birth defects, infertility and genetic disorders in humans.² These findings raised the possibility that the stringency of SAC may be reduced during female meiosis I.^3-5 Sebestova, et al. now provide new evidence that SAC can tolerate misaligned chromosomes in mouse oocytes.⁶

Figure 1. Schematic of the spindle assembly checkpoint pathway. The spindle assembly checkpoint (SAC) controls cell cycle progression during mitosis and meiosis. The anaphase-promoting complex/cyclosome (APC/C) promotes anaphase onset by targeting cyclin B and securin for degradation by the proteasome. If chromosomes are not attached to microtubules, then the SAC inhibits the APC/C and the cell delays anaphase onset to provide more time for proper attachment of kinetochores to microtubules.

Sebestova, et al. used elegant confocal live-cell imaging experiments to monitor chromosome movements, spindle assembly, APC activity and polar body extrusion in mouse oocytes with high rate of aneuploidy. The authors took advantage of the fact that oocytes isolated from aged mice and hybrid oocytes (Mus musculus x Mus spretus) exhibit high rates of chromosomal abnormalities. A series of careful analyses led to several important observations. First, they found that the presence of univalent chromosomes does not delay the onset of anaphase I in oocytes isolated from aged mice.⁶ Importantly, in the presence of nocodazole, which depolymerizes microtubules and induces SAC-dependent arrest, oocytes arrested in meiosis I, indicating that the SAC was functional. This suggests that the stringency of SAC is reduced during female meiosis I or, alternatively, that univalents are able to satisfy the SAC by forming bi-polar (amphitelic or merotelic) attachments.^7-9

Sebestova, et al. further noticed that oocytes isolated from aged mice and hybrid oocytes often (up to 85%) contained unaligned chromosomes (these are chromosomes that presumably failed to establish proper microtubule-kinetochore attachments) at the time of anaphase I onset, as indicated by securin degradation. In fact, about 50% of DNA was positioned outside of the central quarter of the spindle shortly before the onset of anaphase I in hybrid oocytes.⁶ These are significant observations, because the importance of the alignment of chromosomes at the equatorial plane for satisfying the SAC is a matter of debate. Although there are claims that alignment of all chromosomes on the equatorial plane of the spindle is required for satisfying the SAC, other results suggest that the SAC is not sensitive to the position of a chromosome on the spindle.¹

Since the production of normal offspring requires accurate chromosome segregation, it is difficult to understand why female meiosis is unable to efficiently detect and correct aberrant chromosome behaviors. This topic will undoubtedly remain the focus of many future studies. It will also be important to establish to what extent the weakening of the SAC with age contributes to maternal age-related aneuploidy.²