Institute of Biomedicine, Integrative Physiology and Pharmacology Unit, University of Turku, Turku, Finland.
Turku Center for Disease Modeling, University of Turku, Turku, Finland.
Nucleic Acids Res. 2022 Nov 11;50(20):11470-11491. doi: 10.1093/nar/gkac900.
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.
无意义介导的 RNA 衰减（NMD）是一种高度保守且具有选择性的 RNA 降解途径，依赖于内切酶 SMG6。在这里，我们表明 SMG6 对于小鼠的生殖细胞分化是必不可少的。SmG6 的生殖细胞条件性敲除（cKO）导致广泛的转录组失调，包括早期单倍体细胞中无法消除减数分裂表达的转录本，以及具有长 3'非翻译区（UTR）的 NMD 靶 mRNA 的积累。雄性生殖细胞中 SMG6 的缺失导致精子发生在早期单倍体细胞阶段完全停滞。我们发现 SMG6 在染色质体（CB）中显著富集，CB 是雄性生殖细胞中的一种特殊细胞质颗粒，也含有 PIWI 相互作用 RNA（piRNA）和 piRNA 结合蛋白 PIWIL1。这提出了 SMG6 和 piRNA 途径可能共同发挥作用的可能性，这得到了几项发现的支持，包括 Piwil1-KO 小鼠与 Smg6-cKO 小鼠表型相似，以及 SMG6 和 PIWIL1 共同调节圆形精母细胞中的许多基因。总之，我们的研究结果表明 SMG6 是雄性生殖细胞转录组的重要调节剂，并强调 CB 作为一个分子平台，协调 RNA 调节途径以控制精子发生和生育能力。
