title: Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity.
abstract: 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.
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Meng-Wen
authors.initials: MW
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Tie-Gang
authors.initials: TG
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zong-Zhe
authors.initials: ZZ
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ming-Zhe
authors.initials: MZ
authors.lastname: Dong
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, United States of America.
authors.forename: Heide
authors.initials: H
authors.lastname: Schatten
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Qing-Yuan
authors.initials: QY
authors.lastname: Sun
mesh_terms: D000818:Animals; D005260:Female; D005298:Fertility / Q000235:genetics*; D042822:Genomic Instability; D008540:Meiosis / Q000235:genetics; D049469:Meiotic Prophase I / Q000235:genetics; D051379:Mice; D009865:Oocytes / Q000254:growth & development* / Q000378:metabolism; D009866:Oogenesis / Q000235:genetics; D006080:Ovarian Follicle / Q000254:growth & development* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D010766:Phosphorylation; D016649:Primary Ovarian Insufficiency / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6