Stimulus‐specific remodeling of the neuronal transcriptome through nuclear intron‐retaining transcripts

The nuclear envelope has long been considered primarily a physical barrier separating nuclear and cytosolic contents. More recently, nuclear compartmentalization has been shown to have additional regulatory functions in controlling gene expression. A sizeable proportion of protein‐coding mRNAs is more prevalent in the nucleus than in the cytosol, suggesting regulated mRNA trafficking to the cytosol, but the mechanisms underlying controlled nuclear mRNA retention remain unclear. Here, we provide a comprehensive map of the subcellular localization of mRNAs in mature mouse cortical neurons, and reveal that transcripts retained in the nucleus comprise the majority of stable intron‐retaining mRNAs. Systematically probing the fate of nuclear transcripts upon neuronal stimulation, we found opposite effects on sub‐populations of transcripts: while some are targeted for degradation, others complete splicing to generate fully mature mRNAs that are exported to the cytosol and mediate rapid increases in protein levels. Finally, different forms of stimulation mobilize distinct groups of intron‐retaining transcripts, with this selectivity arising from the activation of specific signaling pathways. Overall, our findings uncover a cue‐specific control of intron retention as a major regulator of acute remodeling of the neuronal transcriptome. Synopsis Regulated intron retention represents a mechanism for the control of gene expression. In neurons, this is shown here to affect nuclear retention of mRNAs in response to specific neuronal stimuli. Subcellular mapping of transcripts shows that a large portion of stable intron‐retaining mRNAs is localized to the nucleus. Introns retained in nuclear‐stored transcripts resemble canonically spliced introns and their splicing can be regulated by neuronal stimuli. In response to neuronal stimulation, a subset of intron‐retaining transcripts complete their splicing, are exported to the cytosol, and are recruited for rapid protein synthesis. Distinct sub‐populations of intron‐retaining transcripts are regulated in response to specific neuronal cues. Distinct signaling pathways regulate neuronal stimulus‐dependent regulation of nuclear intron retention transcripts. Graphical Abstract Stored nuclear intron‐retaining transcripts are released into the cytosol upon acute and specific neuronal stimuli, to rapidly increase mRNAs translation and protein synthesis.