Elimination of separase inhibition reveals absence of 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 centromere region 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. It was equally unknown when cohesin protection is put in place and removed. Using structure-function 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 protected early in meiosis I and at metaphase II arrest. Importantly, in meiosis II, the sole event required for cleavage of centromeric cohesin besides separase activation is prior kinetochore individualization in meiosis I.