Prometaphase APCcdh¹ activity prevents non-disjunction in mammalian oocytes

The first female meiotic division (meiosis I, MI) is uniquely prone to chromosome segregation errors through non-disjunction, resulting in trisomies and early pregnancy loss¹. Here, we show a fundamental difference in the control of mammalian meiosis that may underlie such susceptibility. It involves a reversal in the well-established timing of activation of the anaphase-promoting complex (APC)²,³ by its co-activators cdc20 and cdh1. APCcdh¹ was active first, during prometaphase I, and was needed in order to allow homologue congression, as loss of cdh1 speeded up MI, leading to premature chromosome segregation and a non-disjunction phenotype. APCcdh¹ targeted cdc20 for degradation, but did not target securin or cyclin B1. These were degraded later in MI through APCcdc²⁰, making cdc20 re-synthesis essential for successful meiotic progression. The switch from APCcdh¹ to APCcdc²⁰ activity was controlled by increasing CDK1 and cdh1 loss. These findings demonstrate a fundamentally different mechanism of control for the first meiotic division in mammalian oocytes that is not observed in meioses of other species