Tan Xiao, Chen Chengyan, Gao Xiyao, Wang Hua, Zhang Youming, Li Tangliang
State Key Laboratory of Microbial Technology, Shandong University-Qingdao Campus, Qingdao, P.R. China.
Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, P.R. China.
FASEB J. 2024 Dec 13;38(24):e70268. doi: 10.1096/fj.202402422R.
Mammalian spermatogenesis is a tightly controlled cellular process including spermatogonial development and differentiation, meiosis of spermatocyte, and the morphological specification of haploid spermatozoa, during which the post-transcriptional gene regulations are vital but poorly understood. Nonsense-mediated mRNA decay (NMD), a highly conserved post-transcriptional regulatory mechanism of gene expression in eukaryotes, recently emerges as a licensing mechanism in cell fate transition, including stem cell differentiation and organogenesis. The function of NMD in spermatogonial development remains elusive. Here we found knockout of SMG5, an important component of the NMD machinery, in embryonic germ cells led to the failure of spermatogenesis and male infertility. SMG5 null resulted in defective differentiation and maintenance of spermatogonia, which affected initiation of meiosis, ultimately caused a "Sertoli cell-only" phenotype. Transcriptome analysis revealed that SMG5 loss led to serious defects in NMD with targets features including PTC, long 3' UTR, and 5' uORFs. Furthermore, SMG5 loss downregulates gene transcripts involved in spermatogonia expansion and differentiation. During the spermatogonial differentiation, the deletion of SMG5 led to hyperactivation of the p38 MAPK signaling pathway, which triggered widespread cell death. These results suggest that SMG5 mediated NMD plays an important role in spermatogenesis by regulating the p38 MAPK signaling pathway.
哺乳动物精子发生是一个受到严格调控的细胞过程，包括精原细胞的发育与分化、精母细胞的减数分裂以及单倍体精子的形态形成，在此过程中，转录后基因调控至关重要，但目前人们对此了解甚少。无义介导的mRNA降解（NMD）是真核生物中一种高度保守的基因表达转录后调控机制，最近它作为一种细胞命运转变的许可机制出现，包括干细胞分化和器官发生。NMD在精原细胞发育中的功能仍不清楚。在这里，我们发现胚胎生殖细胞中NMD机制的一个重要组成部分SMG5基因敲除会导致精子发生失败和雄性不育。SMG5基因缺失导致精原细胞分化和维持出现缺陷，影响减数分裂的起始，最终导致“唯支持细胞”表型。转录组分析表明，SMG5缺失导致NMD出现严重缺陷，其靶标特征包括PTC、长3'UTR和5' uORF。此外，SMG5缺失会下调参与精原细胞增殖和分化的基因转录本。在精原细胞分化过程中，SMG5的缺失导致p38 MAPK信号通路过度激活，从而引发广泛的细胞死亡。这些结果表明，SMG5介导的NMD通过调节p38 MAPK信号通路在精子发生中发挥重要作用。
