Abstract
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.
Keywords:
alternative splicing; immediate early gene; intron retention; neuronal activity; nuclear export.