Loss of protein phosphatase 6 in oocytes causes failure of meiosis II exit and impaired female fertility.
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.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100101, China.
Meng-Wen
MW
Hu
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Zhen-Bo
ZB
Wang
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
Yan
Y
Teng
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100101, China.
Zong-Zhe
ZZ
Jiang
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Xue-Shan
XS
Ma
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
Ning
N
Hou
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
Xuan
X
Cheng
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
Heide
H
Schatten
Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing 100048, China Xingzhi_Xu@mail.cnu.edu.cn yangx@bmi.ac.cn sunqy@ioz.ac.cn.
Xingzhi
X
Xu
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China Xingzhi_Xu@mail.cnu.edu.cn yangx@bmi.ac.cn sunqy@ioz.ac.cn.
Xiao
X
Yang
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China Xingzhi_Xu@mail.cnu.edu.cn yangx@bmi.ac.cn sunqy@ioz.ac.cn.
Qing-Yuan
QY
Sun
D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000502:physiology*; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009865:Oocytes / Q000166:cytology / Q000201:enzymology*; D009866:Oogenesis / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6
Aneuploidy; Aurora A; Conditional knockout; MII exit; Oocyte; PP6