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The Journal of neuroscience : the official journal of the Society for Neuroscience
Apr 17, 2024;44 (16):

Single-Cell Analysis of Rohon-Beard Neurons Implicates Fgf Signaling in Axon Maintenance and Cell Survival.

Adam M Tuttle, Lauren N Miller, Lindsey J Royer, Hua Wen, Jimmy J Kelly, Nicholas L Calistri, Laura M Heiser, Alex V Nechiporuk
Author Information
  1. Adam M Tuttle: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239. ORCID
  2. Lauren N Miller: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
  3. Lindsey J Royer: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
  4. Hua Wen: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
  5. Jimmy J Kelly: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
  6. Nicholas L Calistri: Biomedical Engineering, Oregon Health & Science University, Portland, Oregon 97239. ORCID
  7. Laura M Heiser: Biomedical Engineering, Oregon Health & Science University, Portland, Oregon 97239.
  8. Alex V Nechiporuk: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 nechipor@ohsu.edu.
PMID: 38423763 DOI: 10.1523/JNEUROSCI.1600-23.2024

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 makeup 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 nonoverlapping 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.

Keywords

Rohon–Beard neuron Sarm1 dovitinib fgf signaling sensory axons sensory neuropathy

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Grants

  1. R01 NS111419/NINDS NIH HHS
  2. R21 CA260025/NCI NIH HHS
  3. T32 CA254888/NCI NIH HHS

MeSH Term

Animals
Zebrafish
Animals, Genetically Modified
Cell Survival
Sensory Receptor Cells
Axons
Single-Cell Analysis
Mammals
Journal Article
Article has an altmetric score of 1

Word Cloud

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