Single-cell analysis of Rohon-Beard neurons implicates Fgf signaling in axon maintenance and cell survival

Abstract

Peripheral sensory neurons are a critical part of the nervous system that transmit a multitude of sensory stimuli to the central nervous system. During larval and juvenile stages in zebrafish, this function is mediated by Rohon-Beard somatosensory neurons (RBs). RBs are optically accessible and amenable to experimental manipulation, making them a powerful system for mechanistic investigation of sensory neurons. Previous studies provided evidence that RBs fall into multiple subclasses; however, the number and molecular make up of these potential RB subtypes have not been well defined. Using a single-cell RNA sequencing (scRNA-seq) approach, we demonstrate that larval RBs in zebrafish fall into three, largely non-overlapping classes of neurons. We also show that RBs are molecularly distinct from trigeminal neurons in zebrafish. Cross-species transcriptional analysis indicates that one RB subclass is similar to a mammalian group of A-fiber sensory neurons. Another RB subclass is predicted to sense multiple modalities, including mechanical stimulation and chemical irritants. We leveraged our scRNA-seq data to determine that the fibroblast growth factor (Fgf) pathway is active in RBs. Pharmacological and genetic inhibition of this pathway led to defects in axon maintenance and RB cell death. Moreover, this can be phenocopied by treatment with dovitinib, an FDA-approved Fgf inhibitor with a common side effect of peripheral neuropathy. Importantly, dovitinib-mediated axon loss can be suppressed by loss of Sarm1, a positive regulator of neuronal cell death and axonal injury. This offers a molecular target for future clinical intervention to fight neurotoxic effects of this drug.

Complete persistence of the primary somatosensory system in zebrafish

“…Do RBs and DRG neurons complement each other functionally? In zebrafish, DRGs and RBs express a shared set of receptors and signaling molecules related to their somatosensory function, including NTRKs, purinergic receptors, scn8aa/Nav1.6, and PKCa (Kucenas et al, 2006;Martin et al, 1998;Palanca et al, 2013;Patten et al, 2007;Pineda et al, 2006;Tuttle et al, 2023;Won et al, 2012). Both RBs and DRGs innervate the skin and specialized structures such as the pectoral fin and scales (Henderson et al, 2020(Henderson et al, , 2019O'Brien et al, 2012;Rasmussen et al, 2018), and their sensory processes overlap substantially (Wright and Ribera, 2010).…”

Fishing Innate Immune System Properties through the Transcriptomic Single-Cell Data of Teleostei

“…We found eight scRNAseq experiments with fish neuronal tissues that were suitable for studying the properties of glial cells in various organs: E-CURD-123 (cranial neural crest, juvenile) [101], GSE105010 (brain, juvenile) [128], GSE132166 (oligodendrocyte precursor cells, larvae) [129], GSE164772 (microglia, juvenile) [93], GSE212314 (telencephalon, juvenile) [90], GSE218107 (neuronal retina, larvae) [130], GSE240026 (spinal cord, embryo) [131], GSE241296 (neurons and glia, larvae) [132].…”