Initial spindle positioning at the oocyte center protects against incorrect kinetochore-microtubule attachment and aneuploidy in mice

Spindle positioning within the oocyte must be regulated tightly. Following nuclear envelope breakdown (NEBD), the spindle is predominantly assembled at the oocyte center prior to its migration towards the cortex to achieve the highly asymmetric division, a characteristic of female meiosis. The significance of the initial central positioning of the spindle is largely unknown. Here we show that the centered spindle in mouse oocytes is an insurance mechanism to avoid the premature exposure to cortical CDC42 signaling, which perturbs proper kinetochore-microtubule attachments, leading to the formation of aneuploid gametes. Because the spindle forms where NEBD occurs, nucleus position significantly influences the location of the initial spindle assembly. We also find that this nucleus positioning is a dynamic process that depends on maternal age. These findings will help in understanding why female gametes are notoriously associated with high rates of aneuploidy, the leading genetic cause of miscarriage and congenital abnormalities.