hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons.
hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons.
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DOI：
10.1073/pnas.1721670115
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发表时间：
2018-03-20
影响因子：
11.1
通讯作者：
Sendtner M
中科院分区：
文献类型：
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作者：
Briese M;Saal-Bauernschubert L;Ji C;Moradi M;Ghanawi H;Uhl M;Appenzeller S;Backofen R;Sendtner M
神经元是高度极化的细胞。rna结合蛋白通过产生不同的亚细胞转录组来促进这种极化。rna结合蛋白hnRNP R对运动神经元轴突生长至关重要。本研究报道了hnRNP R的RNA相互作用组，hnRNP R的主要相互作用RNA为非编码RNA 7SK。原代运动神经元中7SK的缺失干扰了轴突的生长。这种作用依赖于7SK与hnRNP R的相互作用。hnRNP R和7SK都定位于轴突。我们的数据表明，7SK除了在转录调控中发挥作用外，还与hnRNP R一起将特定的转录本分类到轴突中。干扰RNA加工和亚细胞运输有助于运动神经元疾病的病理机制，如肌萎缩侧索硬化症和脊髓性肌萎缩症。rna结合蛋白参与了这些过程，但它们调节转录组亚细胞多样性的机制，特别是轴突的机制，尚不清楚。异质核核糖核蛋白R （hnRNP R）与参与运动神经元疾病的几种蛋白质相互作用。它位于发育中的运动神经元的轴突中，其耗竭会导致轴突生长缺陷。在这里，我们使用单个核苷酸分辨率交联和免疫沉淀（iCLIP）来确定hnRNP R在运动神经元中的RNA相互作用。我们确定了约3500个RNA靶点，主要与突触传递和轴突引导有关。在iCLIP鉴定的RNA靶点中，非编码RNA 7SK是hnRNP r的顶层相互作用物，我们在细胞核和运动神经元的胞浆中也检测到7SK。在轴突中，7SK定位在hnRNP R附近，hnRNP R的缺失降低了轴突7SK。此外，7SK的抑制导致轴突生长缺陷，并伴随轴突转录组改变，类似于hnRNP R缺失引起的改变。通过一系列7SK缺失突变体，我们发现7SK在轴突伸长中的功能取决于其与hnRNP R的相互作用，而不是与参与转录调控的PTEF-B复合体的相互作用。这些结果表明，7SK作为hnRNP R的重要相互作用因子，在轴突维持中调节其功能。
Neurons are highly polarized cells. RNA-binding proteins contribute to this polarization by generating diverse subcellular transcriptomes. The RNA-binding protein hnRNP R is essential for axon growth in motoneurons. This study reports the RNA interactome for hnRNP R. The main interacting RNA of hnRNP R was the noncoding RNA 7SK. Depletion of 7SK from primary motoneurons disturbed axon growth. This effect was dependent on the interaction of 7SK with hnRNP R. Both hnRNP R and 7SK localize to axons. Loss of 7SK led to a similar depletion of axonal transcripts as loss of hnRNP R. Our data suggest that 7SK, in addition to its role in transcriptional regulation, acts in concert with hnRNP R to sort specific transcripts into axons. Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance.
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DOI：
10.1038/nrm3918
发表时间：
2015-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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DOI：
10.1073/pnas.1008227107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Ling, Shuo-Chien;Albuquerque, Claudio P.;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
影响因子：
4.5
作者：
Hogg, J. Robert;Collins, Kathleen
通讯作者：
Collins, Kathleen
影响因子：
64.8
作者：
Nguyen, VT;Kiss, TS;Bensaude, O
通讯作者：
Bensaude, O
影响因子：
16.8
作者：
通讯作者：
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