title: Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity.
abstract: 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.
authors.affiliation: Biozentrum of the University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland.
authors.forename: Oriane
authors.initials: O
authors.lastname: Mauger
authors.affiliation: GenoSplice Technology, iPEPS-ICM, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lemoine
authors.affiliation: Biozentrum of the University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland. Electronic address: peter.scheiffele@unibas.ch.
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D007438:Introns; D051379:Mice; D019579:Neocortex / Q000378:metabolism*; D011061:Poly A / Q000378:metabolism*; D012326:RNA Splicing; D034443:RNA Transport; D012333:RNA, Messenger / Q000378:metabolism*; D012335:RNA, Ribosomal; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D012335:RNA, Ribosomal; D016194:Receptors, N-Methyl-D-Aspartate; D011061:Poly A; D017871:Calcium-Calmodulin-Dependent Protein Kinases
keywords: Ca2+/calmodulin-dependent protein kinase; CaMK; NMDA receptor; activity-dependent gene expression; immediate early gene; intron retention; plasticity; splicing; synapse