RNA regulation in the nervous system: CircRNA expression changes during aging, and function of the Calm1 extended 3′ UTR isoform.

Post-transcriptional regulation provides opportunities to affect RNA dynamicsafter transcription. As most cells within an organism have the same genome, regulationof RNA plays an important role in creating, and maintaining, different cell types such asepithelial cells and neurons. The nervous system is a complicated structure with acorrespondingly complex transcriptome, composed of both coding and non-codingRNAs. One type of RNA adding to the complex neural transcriptome are circular RNAs(circRNAs). These enigmatic transcripts are found in many organisms, ranging fromprokaryotes to humans, but their prevalence was not recognized until recently. CircRNAsare stable, generated from protein coding genes via splicing, and regulate cellularprocesses post-transcriptionally. We found that hundreds of circRNAs accumulated inthe aging mouse brain, but not in the heart. As this trend was specific for the nervoussystem, we speculate that circRNAs are regulated by neural factors, and may play afunctional role in the brain. Another component of the transcriptome are messengerRNAs (mRNAs), which are often regulated by cis- and trans-factors acting on the 3′UTR. Sequences contained within the 3′ UTR can influence translation, stability, orlocalization of a given mRNA. Through the process of alternative cleavage andpolyadenylation (APA), an individual gene can make more than one possible 3′ UTR,including short and long 3′ UTR isoforms. The brain is particularly enriched for long 3′UTRs compared to other tissues, however there have been few in vivo examplesdemonstrating the function of long 3′ UTRs. To better understand what role these long 3′UTRs play in the nervous system, we focused on one example, Calmodulin1. UsingCRISPR/Cas9 genome editing we created an allelic series of deletion mutants targetingthe long 3′ UTR of Calm1 in mice. We found the extended 3′ UTR is important for properdevelopment of several neural populations, including the dorsal root ganglion (DRG) andthe vagus nerve. Together, these studies have found new trends and roles for neurallyenriched RNAs. Our work showed circRNA expression levels are elevated in the agingmouse brain, which may suggest circRNAs play a role in age-related decline of thenervous system. Additionally, we found an in vivo role for a long 3′ UTR isoform in thedeveloping brain. Our study demonstrates the importance of studying long 3′ UTRs invivo, and indicates that further research into the in vivo functions of APA events in thenervous system are warranted