Abstract
Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA turnover pathway that depends on the endonuclease SMG6. Here, we show that SMG6 is essential for male germ cell differentiation in mice. Germ-cell conditional knockout (cKO) of Smg6 induces extensive transcriptome misregulation, including a failure to eliminate meiotically expressed transcripts in early haploid cells, and accumulation of NMD target mRNAs with long 3' untranslated regions (UTRs). Loss of SMG6 in the male germline results in complete arrest of spermatogenesis at the early haploid cell stage. We find that SMG6 is strikingly enriched in the chromatoid body (CB), a specialized cytoplasmic granule in male germ cells also harboring PIWI-interacting RNAs (piRNAs) and the piRNA-binding protein PIWIL1. This raises the possibility that SMG6 and the piRNA pathway function together, which is supported by several findings, including that Piwil1-KO mice phenocopy Smg6-cKO mice and that SMG6 and PIWIL1 co-regulate many genes in round spermatids. Together, our results demonstrate that SMG6 is an essential regulator of the male germline transcriptome, and highlight the CB as a molecular platform coordinating RNA regulatory pathways to control sperm production and fertility.
Original language | English |
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Pages (from-to) | 11470-11491 |
Number of pages | 22 |
Journal | Nucleic Acids Research |
Volume | 50 |
Issue number | 20 |
DOIs | |
Publication status | Published - 11 Nov 2022 |
MoE publication type | A1 Journal article-refereed |
Keywords
- Animals
- Male
- Mice
- Germ Cell Ribonucleoprotein Granules
- Germ Cells/metabolism
- RNA, Small Interfering/genetics
- Spermatids/metabolism
- Spermatogenesis/genetics
- Transcriptome
- Endoribonucleases/metabolism