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

PLoS Genet. 2016 Dec 8;12(12):e1006513. doi: 10.1371/journal.pgen.1006513. eCollection 2016 Dec.

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.

MeSH terms

  • Animals
  • Female
  • Fertility / genetics*
  • Genomic Instability
  • Meiosis / genetics
  • Meiotic Prophase I / genetics
  • Mice
  • Oocytes / growth & development*
  • Oocytes / metabolism
  • Oogenesis / genetics
  • Ovarian Follicle / growth & development*
  • Ovarian Follicle / metabolism
  • Phosphoprotein Phosphatases / genetics*
  • Phosphorylation
  • Primary Ovarian Insufficiency / genetics
  • Primary Ovarian Insufficiency / pathology
  • Signal Transduction

Substances

  • Phosphoprotein Phosphatases
  • protein phosphatase 6

Grants and funding

This work was supported by National Key R&D Program of China [grant number 2016YFC1000600] and the National Natural Science Foundation of China [grant number 31530049, 31671559]. QYS and ZBW received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.