Biozentrum of the University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland.
GenoSplice Technology, iPEPS-ICM, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.
Neuron. 2016 Dec 21;92(6):1266-1278. doi: 10.1016/j.neuron.2016.11.032.
Activity-dependent transcription has emerged as a major source of gene products that regulate neuronal excitability, connectivity, and synaptic properties. However, the elongation rate of RNA polymerases imposes a significant temporal constraint for transcript synthesis, in particular for long genes where new synthesis requires hours. Here we reveal a novel, transcription-independent mechanism that releases transcripts within minutes of neuronal stimulation. We found that, in the mouse neocortex, polyadenylated transcripts retain select introns and are stably accumulated in the cell nucleus. A subset of these intron retention transcripts undergoes activity-dependent splicing, cytoplasmic export, and ribosome loading, thus acutely releasing mRNAs in response to stimulation. This process requires NMDA receptor- and calmodulin-dependent kinase pathways, and it is particularly prevalent for long transcripts. We conclude that regulated intron retention in fully transcribed RNAs represents a mechanism to rapidly mobilize a pool of mRNAs in response to neuronal activity.
活性依赖型转录已成为调节神经元兴奋性、连接性和突触特性的基因产物的主要来源。然而，RNA 聚合酶的延伸速度对转录物的合成施加了显著的时间限制，特别是对于需要数小时才能完成新合成的长基因。在这里，我们揭示了一种新的、不依赖转录的机制，该机制可以在神经元刺激后的几分钟内释放转录物。我们发现，在小鼠新皮层中，多聚腺苷酸化的转录本保留了特定的内含子，并在细胞核中稳定积累。这些内含子保留转录本的一部分经历活性依赖性剪接、细胞质输出和核糖体加载，从而在刺激时急性释放 mRNA。这个过程需要 NMDA 受体和钙调蛋白依赖性激酶途径，并且对于长转录本尤其普遍。我们的结论是，完全转录的 RNA 中的调控内含子保留代表了一种机制，可以快速动员一组 mRNA 以响应神经元活动。
