Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans
Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans
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主要剪接体缺陷导致男性不育，并与人类非梗阻性无精子症相关
DOI：
10.1073/pnas.1513682113
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发表时间：
2016-04-12
影响因子：
11.1
通讯作者：
Xia, Laixin
中科院分区：
文献类型：
--
作者：
Wu, Hao;Sun, Liwei;Xia, Laixin
主要剪接体是mRNA加工所必需的，被认为是细胞生存所必需的。在这里，我们报告了影响主要剪接体的突变与非阻塞性无精子症（NOA）有关，NOA是人类男性不育的常见但知之甚少的原因。具体来说，我们报告说，剪接体失调损害精原细胞的分化，废除成熟的生殖细胞成精子。精原细胞分化过程中对主要剪接体的需求在物种之间高度保守。我们的研究揭示了NOA的遗传原因和分子机制;这些结果可能会为NOA患者的基因检测和治疗提供指导。真核生物中前体mRNA加工成mRNA是一个重要的调控机制，剪接体是一个巨大的动态核糖核蛋白复合体。剪接缺陷与一系列人类疾病有关，但潜在的机制联系在很大程度上仍未得到解决。利用全基因组关联方法，我们最近发现了人类单核苷酸多态性与非阻塞性无精子症（NOA）相关，NOA是男性不育的常见原因。在这里，使用相应的候选基因座在果蝇的遗传操作，我们表明，剪接体组件SNRPA 1/U2 A是必不可少的男性生育能力。果蝇睾丸生殖细胞中U2 A的缺失不影响生殖系干细胞，但确实导致有丝分裂精原细胞的积累，这些精原细胞不能分化成精母细胞和成熟精子。缺乏U2 A导致生殖细胞从增殖到分化的转变所需的mRNA剪接不足。我们发现，生殖细胞特异性破坏的主要剪接体的其他组件表现出相同的表型，表明mRNA加工是精原细胞分化所需的。这种要求是保守的，并且人SNRPA 1的表达完全恢复了U2 A突变果蝇中的精子发生。我们进一步报道了几个错义突变在人类SNRPA 1，抑制组装的主要剪接体显性干扰果蝇精原细胞分化。总的来说，我们的研究结果揭示了一个保守的和具体的要求，主要剪接体在从精原细胞增殖的男性睾丸分化的过渡，这表明剪接体缺陷影响人类精原细胞的分化有助于NOA。
Significance The major spliceosome is required for mRNA processing and is believed to be essential for cell survival. Here we report that mutations affecting the major spliceosome are associated with nonobstructive azoospermia (NOA), a common but poorly understood cause of male infertility in humans. Specifically, we report that spliceosome dysregulation impairs the differentiation of spermatogonia, abolishing the maturation of germ cells into sperm. The requirement for the major spliceosome during spermatogonial differentiation is highly conserved among species. Our study has uncovered genetic causes and molecular mechanisms underlying NOA; these results will likely provide direction for the genetic testing and treatment of patients with NOA. Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Here, using genetic manipulation of corresponding candidate loci in Drosophila, we show that the spliceosome component SNRPA1/U2A is essential for male fertility. Loss of U2A in germ cells of the Drosophila testis does not affect germline stem cells, but does result in the accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes and mature sperm. Lack of U2A causes insufficient splicing of mRNAs required for the transition of germ cells from proliferation to differentiation. We show that germ cell-specific disruption of other components of the major spliceosome manifests with the same phenotype, demonstrating that mRNA processing is required for the differentiation of spermatogonia. This requirement is conserved, and expression of human SNRPA1 fully restores spermatogenesis in U2A mutant flies. We further report that several missense mutations in human SNRPA1 that inhibit the assembly of the major spliceosome dominantly disrupt spermatogonial differentiation in Drosophila. Collectively, our findings uncover a conserved and specific requirement for the major spliceosome during the transition from spermatogonial proliferation to differentiation in the male testis, suggesting that spliceosome defects affecting the differentiation of human spermatogonia contribute to NOA.