Oscillations in PP1 activity are essential for accurate progression through mammalian oocyte meiosis

Tightly controlled fluctuations in kinase and phosphatase activity play important roles in regulating M-phase transitions. Protein Phosphatase 1 (PP1) is one of these phosphatases, with oscillations in PP1 activity driving mitotic M-phase. Evidence from a variety of experimental systems also points to roles in meiosis. Here, we report that PP1 is important for M-phase transitions through mouse oocyte meiosis. We employed a unique small-molecule approach to inhibit or activate PP1 at distinct phases of mouse oocyte meiosis. These studies show that temporal control of PP1 activity is essential for the G2/M transition, metaphase I/anaphase I transition, and the formation of a normal metaphase II oocyte. Our data also reveal that inappropriate activation of PP1 is more deleterious at the G2/M transition than at prometaphase I-to-metaphase I, and that an active pool of PP1 during prometaphase is vital for metaphase I/anaphase I transition and metaphase II chromosome alignment. Taken together, these results establish that loss of oscillations in PP1 activity causes a range of severe meiotic defects, pointing to essential roles for PP1 in female fertility, and more broadly, M-phase regulation.

激酶与磷酸酶活性的严格受控波动，在调控M期转换过程中发挥关键作用。蛋白磷酸酶1（Protein Phosphatase 1，PP1）即属于这类磷酸酶，其活性的周期性波动驱动有丝分裂M期进程。多项实验体系的研究证据亦表明，PP1在减数分裂中同样具有功能。本研究证实，PP1在小鼠卵母细胞减数分裂的M期转换过程中发挥重要作用。我们采用一种独特的小分子干预策略，在小鼠卵母细胞减数分裂的不同阶段对PP1进行抑制或激活操作。研究结果显示，对PP1活性的时序调控，对于G2/M期转换、中期I/后期I转换以及正常中期II卵母细胞的形成均不可或缺。本研究数据还揭示，相较于前中期I向中期I的进程，G2/M期转换阶段PP1的异常激活会造成更为严重的损伤；而前中期阶段存在的活性PP1库，对于中期I/后期I转换以及中期II的染色体列队至关重要。综合来看，本研究结果证实，PP1活性周期性波动的缺失会引发一系列严重的减数分裂异常，这表明PP1在雌性生育能力以及更广泛的M期调控中均发挥不可或缺的作用。