Members of the CUGBP Elav-Like Family of RNA-Binding Proteins are Expressed in Distinct Populations of Primary Sensory Neurons

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ABSTRACT Primary sensory Dorsal Root Ganglia (DRG) neurons are diverse, with distinct populations that respond to specific stimuli. Previously, we observed that functionally distinct populations of DRG neurons express mRNA transcript variants with different 3’ untranslated regions (3’UTR’s). 3’UTRs harbor binding sites for interaction with RNA-binding proteins (RBPs) for transporting mRNAs to subcellular domains, modulating transcript stability and regulating the rate of translation. In the current study, analysis of publicly available single-cell RNA-Sequencing (scRNA-Seq) data generated from adult mice revealed that 17 3’UTR-binding RBPs were enriched in specific populations of DRG neurons. This included 4 members of the CUGBP Elav-Like Family (CELF): CELF2 and CELF4 were enriched in peptidergic, CELF6 in both peptidergic and nonpeptidergic and CELF3 in tyrosine hydroxylase-expressing neurons. Immunofluorescence studies confirmed that 60% of CELF4+ neurons are small diameter C fibers and 33% medium diameter myelinated (likely Aδ) fibers and showed that CELF4 is distributed to peripheral termini. Co-expression analyses using transcriptomic data and immunofluorescence revealed that CELF4 is enriched in nociceptive neurons that express GFRA3, CGRP and the capsaicin receptor TRPV1. Re-analysis of published transcriptomic data from macaque DRG revealed a highly similar distribution of CELF members, and re-analysis of single-nucleus RNA sequencing data derived mouse and rat DRG after sciatic injury revealed differential expression of CELFs in specific populations of sensory neurons. We propose that CELF RNA-binding proteins may regulate the fate of mRNAs in populations of nociceptors, and may play a role in pain and/or neuronal regeneration following nerve injury.

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