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.

周围感觉神经元是神经系统的关键部分，它将多种感觉刺激传递到中枢神经系统。在斑马鱼的幼体和幼体阶段，该功能由 Rohon-Beard 体感神经元 (RB) 介导。 RB 具有光学可访问性并且易于实验操作，这使其成为用于感觉神经元机械研究的强大系统。先前的研究提供了证据表明 RB 属于多个亚类；然而，这些潜在 RB 亚型的数量和分子组成尚未明确。使用单细胞 RNA 测序 (scRNA-seq) 方法，我们证明斑马鱼幼虫 RB 分为三个基本不重叠的神经元类别。我们还表明，RB 在分子上与斑马鱼的三叉神经元不同。跨物种转录分析表明，一个 RB 亚类与哺乳动物的 A 纤维感觉神经元相似。另一个 RB 亚类预计能够感知多种模式，包括机械刺激和化学刺激物。我们利用 scRNA-seq 数据确定成纤维细胞生长因子 (Fgf) 通路在 RB 中活跃。该通路的药理学和遗传抑制导致轴突维持缺陷和 RB 细胞死亡。此外，这可以通过多韦替尼治疗来复制，多韦替尼是 FDA 批准的 Fgf 抑制剂，具有周围神经病变的常见副作用。重要的是，多韦替尼介导的轴突丢失可以通过 Sarm1 的丢失来抑制，Sarm1 是神经元细胞死亡和轴突损伤的正调节因子。这为未来对抗该药物神经毒性作用的临床干预提供了分子靶点。