A Functional Protein Hierarchy Safeguards the Neuronal Transcriptome

Abstract

The production of alternative RNA variants contributes to the tissue-specific regulation of gene expression. In the animal nervous system, a systematic shift towards distal sites of transcription termination produces transcript signatures that are crucial for neuron development and function. Here, we report that the highly conserved protein ELAV globally regulates all events of neuronal 3’end processing by directly binding to proximal polyadenylation sites of target mRNAs. We uncover an endogenous strategy of functional gene rescue that safeguards neuronal RNA signatures in a loss-of-function context. When not directly repressed by ELAV, the transcript encoding the ELAV paralogue FNE acquires a mini-exon, generating a new protein able to translocate to the nucleus and rescue neuronal 3’end processing. We propose that EXon-Activated functional Rescue is a more widespread mechanism that ensures robustness of processes regulated by a hierarchy, rather than redundancy, of effectors.