Role of piRNAs in the inactivation of retrotransposons in mice. A. Expression of PIWI proteins and piRNAs during spermatogenesis in mice. After their migration to gonads, primordial germ cells multiply until cessation around 15 dpc (days post-coitus). This is followed by de novo methylation of DNA. Spermatogonia resumes divisions at 3 dpp (days post-partum) and meiosis starts at 10 dpp. The first round haploid spermatids appears at 14 dpp. B. Biogenesis and function of pachytene piRNAs. After leaving the nucleus, the transcripts harboring piRNA clusters generate primary piRNAs which recruit MILI. The endonuclease activity of MILI cleaves its target to give rise to a secondary piRNA. A ping-pong cycle between two MILI proteins may amplify the production of secondary piRNAs. The secondary piRNAs which bind MIWI2 can enter the nucleus and control the DNA methylation of retrotransposons by basepairing with a transcript in course of elongation to recruit an unknown mechanism leading to histone modification and DNA methylation.