MIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA

MIWI, a murine member ofPIWIproteins mostly expressed during male meiosis, is crucial for piRNAbiogenesis, post-transcriptional regulation, and spermiogenesis. However, its meiotic function remains unknown. Here, we report thatMIWIdeficiency alters meiotic kinetochore assembly, significantly increases chromosome misalignment at the meiosis metaphase I plate, and causes chromosome mis-segregation. Consequently,Miwi-deficient mice show elevated aneuploidy in metaphaseIIand spermatid death. Furthermore, inMiwi-null andMiwislicer-deficient mutants, major and minor satelliteRNAs from centromeric and pericentromeric satellite repeats accumulate in excess. Over-expression of satellite repeats in wild-type spermatocytes also causes elevated chromosome misalignment, whereas reduction of both strands of major or minor satelliteRNAs results in lower frequencies of chromosome misalignment. We show thatMIWI, guided by piRNA, cleaves major satelliteRNAs, generatingRNAfragments that may form substrates for subsequent Dicer cleavage. Furthermore, Dicer cleaves all satelliteRNAs in conjunction withMIWI. These findings reveal a novel mechanism in whichMIWI- and Dicer-mediated cleavage of the satelliteRNAs prevents the over-expression of satelliteRNAs, thus ensuring proper kinetochore assembly and faithful chromosome segregation during meiosis.