RBP-Driven RNA Sorting and Local Translation Establish the Molecular Identities of Individual Sensory Axons

Abstract

Neurons extend long axons that traverse distinct microenvironments, yet how these compartments acquire and maintain specialized molecular identities remains unclear. Here, we use spatial translatomics to define the local axonal translatomes of dorsal root ganglion (DRG) neurons that mediate somatosensation. Translating Ribosome Affinity Purification and RNA sequencing revealed thousands of mRNAs that are preferentially translated within the central axons, peripheral axons, or DRG soma, establishing compartment-specific translational programs. Many of these transcripts encode ion channels, neurotransmitter receptors, and structural proteins that confer distinct electrophysiological, synaptic, and regenerative properties to each axon. Cross-dataset integration with single-cell RNA-seq demonstrated that neuropathic injury elicits highly compartment-specific remodeling of these localized translational programs. We identify polarized RNA regulons coordinated by the RNA-binding proteins (RBPs) SFPQ and SRSF10, which preferentially bind and traffic mRNAs to the peripheral or central axon, respectively. These findings reveal a mechanistic framework in which RBP-guided RNA sorting and local translation establish and dynamically tune subcellular specialization in sensory neurons. HIGHLIGHTSO_LIDistinct mRNAs are translated in peripheral or central axons (painseq.shinyapps.io/CompartmentTRAP/). C_LIO_LIAxonal translatomes enable localized regulation of electrophysiology, neuronal plasticity, and regeneration. C_LIO_LIThe RBPs, SFPQ and SRSF10, enable mRNA sorting to peripheral and central axons respectively. C_LI