Mad2 is dispensable for accurate chromosome segregation but becomes essential when oocytes are subjected to environmental stress

Accurate chromosome segregation, monitored by the spindle assembly checkpoint (SAC), is crucial for the production of euploid cells. Previous in vitro studies by us and others showed that Mad2, a core member of the SAC, performs a checkpoint function in oocyte meiosis. Here, through an oocyte-specific knockout approach in mouse, we reconfirmed that Mad2-deficient oocytes exhibit an accelerated metaphase-to-anaphase transition caused by premature degradation of securin and cyclin B1 and subsequent activation of separase in meiosis I. However, it was surprising that the knockout mice were completely fertile and the resulting oocytes were euploid. In the absence of Mad2, other SAC proteins, including BubR1, Bub3 and Mad1, were normally recruited to the kinetochores, which likely explains the balanced chromosome separation. Further studies showed that the chromosome separation in Mad2-null oocytes was particularly sensitive to environmental changes and, when matured in vitro, showed chromosome misalignment, lagging chromosomes, and aneuploidy with premature separation of sister chromatids, which was exacerbated at a lower temperature. We reveal for the first time that Mad2 is dispensable for proper chromosome segregation but acts to mitigate environmental stress in meiotic oocytes.

Automated summary

In this study, the role of Mad2 in meiotic oocytes was investigated using a mouse-specific knockout approach. It was found that Mad2-deficient oocytes exhibited an accelerated metaphase-to-anaphase transition, caused by premature degradation of securin and cyclin B1. However, the knockout mice were still fertile and the resulting oocytes were euploid. Further studies showed that Mad2 acts to mitigate environmental stress in meiotic oocytes and its absence led to chromosome misalignment, lagging chromosomes, aneuploidy, and premature separation of sister chromatids, particularly when matured in vitro at a lower temperature.