Eliminating separase inhibition reveals absence of robust cohesin protection in oocyte metaphase II

Abstract The meiotic segregation pattern to generate haploid gametes is mediated by step-wise cohesion removal by separase, first from chromosome arms in meiosis I, and then from the pericentromere in meiosis II. In mammalian oocytes, separase is tightly controlled during the hours-long prometaphase and until chromosome segregation in meiosis I, activated for a short time window, and again inhibited until metaphase II arrest is lifted by fertilization. Centromeric cohesin is protected from cleavage by Sgo2-PP2A in meiosis I. It remained enigmatic how tight control of alternating separase activation and inactivation is achieved during the two divisions in oocytes, and when cohesin protection is put in place and removed. Using complementation assays in knock-out mouse models, we established the contributions of cyclin B1 and securin for separase inhibition during both divisions. When eliminating separase inhibition, we found that cohesin is not robustly protected at meiosis I resumption and during metaphase II arrest. Importantly, in meiosis II, the sole event required for cleavage of pericentromeric cohesin besides separase activation is prior kinetochore individualization in meiosis I.