Dynamic protein phosphorylation and dephosphorylation, mediated by a conserved cohort of protein kinases and phosphatases, regulate cell cycle progression. Among the well-known PP2A-like protein phosphatases, protein phosphatase 6 (PP6) has been analyzed in mammalian mitosis, and Aurora A has recently been identified as its key substrate. However, the functions of PP6 in meiosis are still entirely unknown. To identify the physiological role of PP6 in female gametogenesis, Ppp6c F/F mice were first generated and crossed with Zp3-Cre mice to selectively disrupt Ppp6c expression in oocytes. Here, we report for the first time that PP6c is dispensable for oocyte meiotic maturation but essential for exit from meiosis II (MII) after fertilization. Depletion of PP6c caused an abnormal MII spindle and disrupted MII cytokinesis, resulting in zygotes with high risk of aneuploidy and defective early embryonic development, and thus severe subfertility. We also reveal that PP6 inactivation interferes with MII spindle formation and MII exit owing to increased Aurora A activity, and that Aurora A inhibition with MLN8237 can rescue the PP6c depletion phenotype. In conclusion, our findings uncover a hitherto unknown role for PP6 as an indispensable regulator of oocyte meiosis and female fertility.

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