Evading non-essential fetal oocyte attrition maximizes the ovarian reserve

Female reproductive success depends on the size and quality of a finite ovarian reserve. Paradoxically, mammals such as mice and humans eliminate up to 80% of the initial oocyte pool during development through the enigmatic process of fetal oocyte attrition (FOA). Here we report that the combined inhibition of retrotransposon L1 reverse transcriptase and the Chk2-dependent DNA damage checkpoint prevents FOA, thus preserving the entire fetal oocyte population. Remarkably, reverse transcriptase inhibitor AZT-treated Chk2 mutant oocytes initially accumulate, but subsequently resolve L1-instigated genotoxic threats and differentiate, resulting in a maximized functional ovarian reserve. We conclude that FOA is a consequence of genotoxic stress that acts to preserve oocyte genome integrity, and is not an obligatory developmental program for oogenesis.