Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability.
Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability.
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DOI：
10.1016/j.neuron.2012.07.009
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发表时间：
2012-09-20
期刊：
影响因子：
16.2
通讯作者：
Darnell RB
中科院分区：
文献类型：
--
作者：
Ince-Dunn G;Okano HJ;Jensen KB;Park WY;Zhong R;Ule J;Mele A;Fak JJ;Yang C;Zhang C;Yoo J;Herre M;Okano H;Noebels JL;Darnell RB
副肿瘤性神经系统疾病靶向神经元特异性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来确定神经元Elav-like（nElavl）RNABP靶向的稳健结合位点。令人惊讶的是，nElav蛋白在体内和体外优先结合富含GU的序列，其次结合富含AU的序列。使用nElavl-缺失小鼠来验证这些结合事件在脑中的结果，证明它们以位置依赖性方式结合内含子序列以调节可变剪接并结合3 'UTR序列以调节mRNA水平。这些控制集中在神经元中的谷氨酸合成途径上; nElavl蛋白是维持神经递质谷氨酸水平所需的，并且nElavl的缺乏导致自发性癫痫发作活动。对nElavl靶标的全基因组分析揭示了神经元特异性RNABP的一个功能是控制大脑中的兴奋-抑制平衡。
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 bind 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.
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影响因子：
14.9
作者：
Bolognani F;Contente-Cuomo T;Perrone-Bizzozero NI
通讯作者：
Perrone-Bizzozero NI
影响因子：
5.3
作者：
Buckanovich, RJ;Darnell, RB
通讯作者：
Darnell, RB
影响因子：
64.5
作者：
Huang, CS;Shi, SH;Jan, LY
通讯作者：
Jan, LY
影响因子：
16.8
作者：
通讯作者：
--
ELAV是果蝇神经元特异性蛋白，可介导产生一种替代剪接的神经蛋白异构体
影响因子：
9.2
作者：
Koushika, SP;Lisbin, MJ;White, K
通讯作者：
White, K