Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity

Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported...

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Bibliographic Details
Published in:PLoS genetics 2016-12, Vol.12 (12), p.e1006513-e1006513
Main Authors: Hu, Meng-Wen, Meng, Tie-Gang, Jiang, Zong-Zhe, Dong, Ming-Zhe, Schatten, Heide, Xu, Xingzhi, Wang, Zhen-Bo, Sun, Qing-Yuan
Format: Article
Language:English
Subjects:
Animals
Arrests
Biology
Biology and Life Sciences
Cell cycle
Cell division
Colleges & universities
Deoxyribonucleic acid
DNA
Female
Females
Fertility - genetics
Funding
Genomic Instability
Genotype & phenotype
Infertility
Kinases
Laboratories
Mammals
Medicine and Health Sciences
Meiosis - genetics
Meiotic Prophase I - genetics
Mice
Oocytes - growth & development
Oocytes - metabolism
Oogenesis - genetics
Ovarian Follicle - growth & development
Ovarian Follicle - metabolism
Phosphatase
Phosphoprotein Phosphatases - genetics
Phosphorylation
Primary Ovarian Insufficiency - genetics
Primary Ovarian Insufficiency - pathology
Proteins
Research and Analysis Methods
Signal Transduction
Stem cells
Zoology
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Summary:Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported that protein phosphatase 6 (PP6), a member of the PP2A-like subfamily, which accounts for cellular serine/threonine phosphatase activity, functions in completing the second meiosis. Here, we generated mutant mice with a specific deletion of Ppp6c in oocytes from the primordial follicle stage by crossing Ppp6cF/F mice with Gdf9-Cre mice and found that Ppp6cF/F; GCre+ mice are infertile. Depletion of PP6c caused folliculogenesis defects and germ cell loss independent of the traditional AKT/mTOR pathway, but due to persistent phosphorylation of H2AX (a marker of double strand breaks), increased susceptibility to DNA damage and defective DNA repair, which led to massive oocyte elimination and eventually premature ovarian failure (POF). Our findings uncover an important role for PP6 as an indispensable guardian of genomic integrity of the lengthy prophase I oocyte arrest, maintenance of primordial follicle pool, and thus female fertility.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006513