M-Phase oscillations in PP1 activity are essential for accurate progression through mammalian oocyte meiosis

Abstract

Tightly controlled fluctuations in kinase and phosphatase activity play important roles in regulating M-Phase transitions (e.g., G2/M). Protein Phosphatase 1 (PP1) is one of these phosphatases, with oscillations in activity driving mitotic M-Phase entry, progression, and exit, with evidence from a variety of experimental systems pointing to roles in meiosis as well. Here we report that PP1 is important for M-Phase transitions through mouse oocyte meiosis. Employing a unique small-molecule approach to inhibit or activate PP1 at distinct phases of mouse oocyte meiosis, we found that aberrations in normal cyclical PP1 activity leads to meiotic abnormalities. We report here that temporal control of PP1 activity is essential for 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 G2/M transition than at prometaphase I-to-metaphase I, and that an active pool of PP1 during prometaphase I 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 oocytes and female fertility, and more broadly, M-Phase regulation.