Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes.
Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes.
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DOI：
10.1261/rna.038919.113
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Matera AG
中科院分区：
文献类型：
--
作者：
Garcia EL;Lu Z;Meers MP;Praveen K;Matera AG
运动神经元存活（SMN）蛋白表达减少导致人类脊髓性肌萎缩（SMA），严重SMA动物模型在病程后期显示前体mRNA剪接缺陷。使用野生型和生存运动神经元（Smn）无效突变幼虫的RNA深度测序（RNA-seq），我们确定了突变体中的发育停滞，该突变体先于剪接中的广泛破坏。Smn突变体的全基因组mRNA表达谱的比较显示，只有微小的含内含子的mRNA水平的变化很小，相反，我们观察到一个显着增加的水平的压力信号转录，这可能是一个保守的功能SMA。运动神经元存活（SMN）蛋白水平降低会导致一种称为脊髓性肌萎缩（SMA）的神经肌肉疾病。SMA的动物模型概括了人类疾病的许多方面，包括运动和生存能力缺陷，但迄今未能揭示缺乏SMN蛋白和神经肌肉功能障碍之间的因果关系。虽然已知SMN组装催化前体mRNA剪接的小核核糖核蛋白（snRNP），但仍不清楚剪接中断是否是SMA的病因。为了研究这个问题，我们对年龄匹配的果蝇Smn-null和野生型幼虫进行了RNA深度测序（RNA-seq）。全基因组mRNA表达谱与公开数据集的比较揭示了Smn突变体发育停滞的时间。此外，野生型和Smn动物之间剪接的全基因组差异与mRNA水平的变化无关。具体来说，我们发现，mRNA水平的基因，含有小内含子的变化更随着发育时间比野生型和Smn突变体之间。读取映射到次要类内含子-外显子连接的分析显示，在Smn幼虫中，在整个发育过程中发生的正常波动内，次要内含子的剪接只有很小的变化。与此相反，Smn突变体显示出显着增加应激反应的转录水平，表明系统性反应的发展停滞诱导的损失SMN蛋白。这些研究结果不仅提供了重要的机制洞察Smn突变体显示的发育停滞，但也反对一个小内含子依赖性SMA的病因。
Reduced expression of the survival motor neuron (SMN) protein causes spinal muscular atrophy (SMA) in humans and animal models of severe SMA display defects in pre-mRNA splicing late in the disease course. Using RNA deep-sequencing (RNA-seq) of wild-type and survival motor neuron (Smn) null mutant larvae, we identified a developmental arrest in the mutants that precedes the onset of widespread disruptions in splicing. Comparison of genome-wide mRNA expression profiles of Smn mutants revealed only small changes in levels of minor intron-containing mRNAs; in contrast, we observed a prominent increase in levels of stress-signaling transcripts that may be a conserved feature of SMA. Reduced levels of survival motor neuron (SMN) protein lead to a neuromuscular disease called spinal muscular atrophy (SMA). Animal models of SMA recapitulate many aspects of the human disease, including locomotion and viability defects, but have thus far failed to uncover the causative link between a lack of SMN protein and neuromuscular dysfunction. While SMN is known to assemble small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing, it remains unclear whether disruptions in splicing are etiologic for SMA. To investigate this issue, we carried out RNA deep-sequencing (RNA-seq) on age-matched Drosophila Smn-null and wild-type larvae. Comparison of genome-wide mRNA expression profiles with publicly available data sets revealed the timing of a developmental arrest in the Smn mutants. Furthermore, genome-wide differences in splicing between wild-type and Smn animals did not correlate with changes in mRNA levels. Specifically, we found that mRNA levels of genes that contain minor introns vary more over developmental time than they do between wild-type and Smn mutants. An analysis of reads mapping to minor-class intron–exon junctions revealed only small changes in the splicing of minor introns in Smn larvae, within the normal fluctuations that occur throughout development. In contrast, Smn mutants displayed a prominent increase in levels of stress-responsive transcripts, indicating a systemic response to the developmental arrest induced by loss of SMN protein. These findings not only provide important mechanistic insight into the developmental arrest displayed by Smn mutants, but also argue against a minor-intron-dependent etiology for SMA.
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影响因子：
3.9
作者：
Biteau, Benoit;Karpac, Jason;Hwangbo, DaeSung;Jasper, Heinrich
通讯作者：
Jasper, Heinrich
影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
影响因子：
3.3
作者：
Shpargel, Karl B.;Praveen, Kavita;Matera, A. Gregory
通讯作者：
Matera, A. Gregory
与电机电路函数必不可少的SMN依赖性U12剪接事件。
影响因子：
64.5
作者：
Lotti F;Imlach WL;Saieva L;Beck ES;Hao le T;Li DK;Jiao W;Mentis GZ;Beattie CE;McCabe BD;Pellizzoni L
通讯作者：
Pellizzoni L
SMN是果蝇中感觉运动电路函数所必需的。
影响因子：
64.5
作者：
Imlach WL;Beck ES;Choi BJ;Lotti F;Pellizzoni L;McCabe BD
通讯作者：
McCabe BD