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首页> 外文期刊>Neuron >Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability
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Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability

机译：神经元类似Elav（Hu）的蛋白质调节RNA剪接和丰度，以控制谷氨酸水平和神经元兴奋性。

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The paraneoplastic neurologic disorders target several families of neuron-specific RNA binding proteins (RNABPs), revealing that there are unique aspects of gene expression regulation in the mammalian brain. Here, we used HITS-CLIP to determine robust binding sites targeted by the neuronal Elav-like (nElavl) RNABPs. Surprisingly, nElav protein binds preferentially to GU-rich sequences in vivo and in vitro, with secondary binding to AU-rich sequences. nElavl null mice were used to validate the consequence of these binding events in the brain, demonstrating that they bind intronic sequences in a position dependent manner to regulate alternative splicing and to 3'UTR sequences to regulate mRNA levels. These controls converge on the glutamate synthesis pathway in neurons; nElavl proteins are required to maintain neurotransmitter glutamate levels, and the lack of nElavl leads to spontaneous epileptic seizure activity. The genome-wide analysis of nElavl targets reveals that one function of neuron-specific RNABPs is to control excitation-inhibition balance in the brain. Video Abstract: RNA processing plays a critical role in neuronal development and disease. Ince-Dunn et al. map genome-wide protein-RNA interactions using HITS-CLIP and KO mice to identify nElavl binding sites that regulate RNA splicing and abundance in brain required for glutamate balance and neuronal excitability.
机译：副肿瘤性神经系统疾病针对神经元特异性RNA结合蛋白（RNABP）的几个家族，揭示了哺乳动物大脑中基因表达调控的独特方面。在这里，我们使用HITS-CLIP确定神经元Elav样（nElavl）RNABPs靶向的牢固结合位点。出人意料的是，nElav蛋白在体内和体外优先与富含GU的序列结合，而与富含AU的序列具有二次结合。 nElavl null小鼠用于验证大脑中这些结合事件的结果，表明它们以位置依赖的方式结合内含子序列以调节可变剪接，并与3'UTR序列结合以调节mRNA水平。这些控制集中在神经元的谷氨酸合成途径上。需要nElavl蛋白来维持神经递质谷氨酸水平，而nElavl的缺乏会导致自发性癫痫发作。 nElavl靶标的全基因组分析表明，神经元特异性RNABP的功能之一是控制大脑中的兴奋抑制平衡。视频摘要：RNA加工在神经元发育和疾病中起关键作用。 Ince-Dunn等。使用HITS-CLIP和KO小鼠定位全基因组蛋白-RNA相互作用，以鉴定调控谷氨酸平衡和神经元兴奋性所需的RNA剪接和大脑中nRNA的结合位点。

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