PNLDC1 catalysis and postnatal germline function are required for piRNA trimming, LINE1 silencing, and spermatogenesis in mice.

PIWI-interacting RNAs (piRNAs) play critical and conserved roles in transposon silencing and gene regulation in the animal germline. Three distinct piRNA populations are present during mouse spermatogenesis: fetal piRNAs in fetal/perinatal testes, pre-pachytene and pachytene piRNAs in postnatal testes. PNLDC1 is required for piRNA 3' end maturation in multiple species. However, whether PNLDC1 is the bona fide piRNA trimmer and the physiological role of 3' trimming of different piRNA populations in spermatogenesis in mammals remain unclear. Here, by inactivating Pnldc1 exonuclease activity in vitro and in mice, we reveal that the PNLDC1 trimmer activity is essential for spermatogenesis and male fertility. PNLDC1 catalytic activity is required for both fetal and postnatal piRNA 3' end trimming. Despite this, postnatal piRNA trimming but not fetal piRNA trimming is critical for LINE1 transposon silencing. Furthermore, conditional inactivation of Pnldc1 in postnatal germ cells causes LINE1 transposon de-repression and spermatogenic arrest in mice, indicating that germline-specific postnatal piRNA trimming is essential for transposon silencing and germ cell development. Our findings highlight the germ cell-intrinsic role of PNLDC1 and piRNA trimming in mammals to safeguard the germline genome and promote fertility. Author summary: PNLDC1 is required for piRNA trimming and is essential for spermatogenesis and male fertility in mice. Loss-of-function mutations in human PNLDC1 cause azoospermia in men. However, the precise functions of PNLDC1 exonuclease activity in piRNA trimming and germ cell development remain unknown. Here we genetically inactivate the trimmer activity of PNLDC1 in mice and show that the catalytic activity of PNLDC1 is critical for male fertility. Strikingly, postnatal germline conditional deletion of Pnldc1 in mice that disrupt pre-pachytene and pachytene piRNA trimming causes transposon activation and male infertility. Collectively, these new genetic models provide the proof-of-principle evidence that ablating the catalytic activity of a key piRNA pathway factor in adult males as a novel strategy for non-hormonal male contraception. [ABSTRACT FROM AUTHOR]