The survival motor neuron gene smn-1 interacts with the U2AF large subunit gene uaf-1 to regulate Caenorhabditis elegans lifespan and motor functions
The survival motor neuron gene smn-1 interacts with the U2AF large subunit gene uaf-1 to regulate Caenorhabditis elegans lifespan and motor functions
复制标题
运动神经元存活基因 smn-1 与 U2AF 大亚基基因 uaf-1 相互作用，调节秀丽隐杆线虫寿命和运动功能
DOI：
10.4161/rna.36100
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发表时间：
2014-09-01
期刊：
影响因子：
4.1
通讯作者：
Ma, Long
中科院分区：
文献类型：
--
作者：
Gao, Xiaoyang;Teng, Yanling;Ma, Long
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是人类最常见的先天性运动神经元退行性疾病，由高度保守的运动神经元生存基因SMN 1的功能缺失突变引起。SMN的突变可能影响几个分子过程，其中由snRNP生物合成缺陷引起的异常前mRNA剪接被假设为SMA的主要原因。迄今为止，很少有人知道SMN与其他剪接因子基因的相互作用，以及SMN如何影响剪接在体内。线虫秀丽隐杆线虫携带SMN的单一直系同源物smn-1，并已被用作研究SMN分子功能的模型。我们分析了smn-1缺失突变体中报告基因的RNA剪接，发现smn-1是在弱3′剪接位点有效剪接所必需的。遗传学研究表明，有缺陷的寿命和运动功能的smn-1缺失突变体可以显着改善剪接因子U2 AF大亚基基因uaf-1的突变。在smn-1突变体中，我们检测到U1和U 5 snRNA的表达减少，U2，U4和U6 snRNA的表达增加。我们的研究证实了smn-1在体内RNA剪接中的重要作用，鉴定了uaf-1基因作为smn-1突变体的潜在遗传修饰因子，并表明SMN-1对剪接体snRNA的表达具有多方面的影响。
Spinal muscular atrophy (SMA), the most frequent human congenital motor neuron degenerative disease, is caused by loss-of-function mutations in the highly conserved survival motor neuron gene SMN1. Mutations in SMN could affect several molecular processes, among which aberrant pre-mRNA splicing caused by defective snRNP biogenesis is hypothesized as a major cause of SMA. To date little is known about the interactions of SMN with other splicing factor genes and how SMN affects splicing in vivo. The nematode Caenorhabditis elegans carries a single ortholog of SMN, smn-1, and has been used as a model for studying the molecular functions of SMN. We analyzed RNA splicing of reporter genes in an smn-1 deletion mutant and found that smn-1 is required for efficient splicing at weak 3′ splice sites. Genetic studies indicate that the defective lifespan and motor functions of the smn-1 deletion mutants could be significantly improved by mutations of the splicing factor U2AF large subunit gene uaf-1. In smn-1 mutants we detected a reduced expression of U1 and U5 snRNAs and an increased expression of U2, U4 and U6 snRNAs. Our study verifies an essential role of smn-1 for RNA splicing in vivo, identifies the uaf-1 gene as a potential genetic modifier of smn-1 mutants, and suggests that SMN-1 has multifaceted effects on the expression of spliceosomal snRNAs.