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Neuron. 2016 Dec 21;92(6):1266-1278. doi: 10.1016/j.neuron.2016.11.032.

Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity.

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Biozentrum of the University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland.
GenoSplice Technology, iPEPS-ICM, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.
Biozentrum of the University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland. Electronic address:


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.


Ca2+/calmodulin-dependent protein kinase; CaMK; NMDA receptor; activity-dependent gene expression; immediate early gene; intron retention; plasticity; splicing; synapse

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