Dgcr8 and Dicer are essential for sex chromosome integrity in male meiosis

Small RNAs play crucial roles in regulating gene expression during mammalian meiosis. To investigate the function of microRNAs and small-interfering RNAs in male meiosis, we generated germ cell-specific conditional deletions of Dgcr8 and Dicer in mice. Analysis of spermatocytes from both conditional knockout lines reveals frequent chromosomal fusions during meiosis, always involving one or both sex chromosomes. RNA sequencing indicates upregulation of Atm in spermatocytes from microRNA-deficient mice, and immunofluorescence imaging demonstrates an increased abundance of activated ATM kinase and mislocalization of phosphoMDC1, an ATM phosphorylation substrate. The Atm 3′UTR contains many potential microRNA target sites; notably, target sites for several miRNAs depleted in both conditional knockout mice are highly effective at promoting repression. RNF8, a telomere-associated protein whose localization is controlled by the MDC1/ATM kinase cascade, normally associates with the sex chromosomes during pachytene, but in both conditional knockouts redistributes to the autosomes. Together, these results suggest that Atm dysregulation in microRNA-deficient germ lines contributes to the redistribution of proteins involved in chromosomal stability from the sex-chromosomes to the autosomes, resulting in sex-chromosome fusions during meiotic prophase I.