Alternative 3’UTRs diversify the mRNA population in neuronal compartments

The morphological complexity of neurons and the spatial compartmentalization of synapses necessitate unique solutions to maintain and modify the dendritic and axonal proteome. One solution that neurons use is to localize mRNAs near synapses where their translation into protein can be regulated by synaptic demand and activity. In recent years, the number of localized dendritic and axonal neuronal transcripts detected has increased dramatically from hundreds to thousands. It is known that differences in the 3’UTRs of mRNAs can give rise to differences in localization, stability, and translational regulation. Using 3’end RNA sequencing together with microdissection of brain slices to examine separately transcripts arising from somata or the neuropil (primarily axons and dendrites), we discovered a huge diversity in the 3’UTRs of neuronal mRNAs, with many transcripts showing enrichment for a particular 3’UTR isoform in a cellular compartment. The 3’UTR isoforms of localized transcripts, enriched in either the neuropil or somata, are significantly longer than the 3’UTRs of non-enriched transcripts and code for proteins associated with neuronal projections (axons and dendrites) and synapses. Surprisingly, the information contained in 3’UTRs includes not only new regulatory elements but also a significant representation of duplicate regulatory elements. The 3’UTR isoforms enriched in the neuropil are endowed with significantly longer half-lives than isoforms enriched in somata. Finally, we observed that 3’UTR isoforms exhibit plasticity: following enhanced neural activity, the 3’UTR isoforms present in the somata and neuropil are significantly altered. Most of the 3’UTR plasticity is transcription-dependent but there remain intriguing examples of changes that are consistent with altered stability, trafficking between compartments or local “remodeling”.