Initial Spindle Positioning at the Oocyte Center Protects Against Incorrect Kinetochore-Microtubule Attachment and Aneuploidy in Mice

Abstract

Spindle formation and positioning are two critical events that must be regulated tightly to avoid erroneous chromosome segregation. Following nuclear envelope breakdown (NEBD), the spindle is predominantly assembled centrally before migrating towards the cortex to allow the first asymmetric division. The biological significance of primary central positioning of the spindle has not yet been studied. Because the spindle forms where NEBD occurs, nucleus position greatly influences the site of spindle assembly. We find that nucleus positioning is a dynamic process that depends on maternal age. Moreover, we show that preferential initial spindle positioning at the oocyte center is an insurance mechanism to avoid premature exposure to cortical Cdc42 signaling that hinders proper kinetochore-microtubule attachments, thereby protecting against the development of aneuploid gametes. These findings will help in understanding why female gametes are notoriously associated with high rates of aneuploidy, the leading genetic cause of miscarriage and infertility in women.