Protein phosphatase 4 maintains the survival of primordial follicles by regulating autophagy in oocytes

In mammalian ovary, the primordial follicle pool serves as the source of developing follicles and fertilizable ova. To maintain the normal length of female reproductive life, the primordial follicles must have adequate number and be kept in a quiescent state before menopause. However, the molecular mechanisms underlying primordial follicle survival are poorly understood. Here, we provide genetic evidence showing that lacking protein phosphatase 4 (PPP4) in oocytes, a member of PP2A-like subfamily, results in infertility in female mice. A large quantity of primordial follicles has been depleted around the primordial follicle pool formation phase and the ovarian reserve is exhausted at about 7 months old. Further investigation demonstrates that depletion of PPP4 causes the abnormal activation of mTOR, which suppresses autophagy in primordial follicle oocytes. The abnormal primordial follicle oocytes are eventually erased by pregranulosa cells in the manner of lysosome invading. These results show that autophagy prevents primordial follicles over loss and PPP4-mTOR pathway governs autophagy during the primordial follicle formation and dormant period.