A Role for Retrotransposon LINE-1 in Fetal Oocyte Attrition in Mice

Fetal oocyte attrition (FOA) is a conserved but poorly understood process of elimination of more than two-thirds of meiotic prophase I (MPI) oocytes before birth. We now implicate retrotransposons LINE-1 (L1), activated during epigenetic reprogramming of the embryonic germline, in FOA in mice. We show that wild-type fetal oocytes possess differential nuclear levels of L1ORF1p, an L1-encoded protein essential for L1 ribonucleoprotein particle (L1RNP) formation and L1 retrotransposition. We demonstrate that experimental elevation of L1 expression correlates with increased MPI defects, FOA, oocyte aneuploidy, and embryonic lethality. Conversely, reverse transcriptase (RT) inhibitor AZT has a profound effect on the FOA dynamics and meiotic recombination, and it implicates an RT-dependent trigger in oocyte elimination in early MPI. We propose that FOA serves to select oocytes with limited L1 activity that are therefore best suited for the next generation. [Display omitted] •Differential nuclear retrotransposon L1 levels in meiotic prophase I fetal oocytes•Increased L1 expression precipitates oocyte genome damage and meiotic defects•AZT implicates RNA/DNA hybrids in triggering oocyte death and chiasma failure•L1 activity underlies fetal oocyte attrition, reduced ovarian reserves, and aneuploidy Over two-thirds of mammalian fetal oocytes are lost prenatally. Malki et al. show that in mice, this fetal oocyte attrition removes oocytes with high activity of retrotransposon L1 that otherwise causes genome damage, meiotic defects, and oocyte aneuploidy. Both the L1 reverse transcriptase and endonuclease activities contribute to oocyte demise.