Prox2 and Runx3 vagal sensory neurons regulate esophageal motility

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 14; pp. 2184 - 2200.e7
• Main Authors: Lowenstein, Elijah D., Ruffault, Pierre-Louis, Misios, Aristotelis, Osman, Kate L., Li, Huimin, Greenberg, Rachel S., Thompson, Rebecca, Song, Kun, Dietrich, Stephan, Li, Xun, Vladimirov, Nikita, Woehler, Andrew, Brunet, Jean-François, Zampieri, Niccolò, Kühn, Ralf, Liberles, Stephen D., Jia, Shiqi, Lewin, Gary R., Rajewsky, Nikolaus, Lever, Teresa E., Birchmeier, Carmen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2023
• Subjects: digestion; esophagus; homeostasis; mechanoreceptors; mechanosensation; motility; peristalsis; single-cell RNA sequencing; vagal afferents; vagus nerve; single-cell RNA sequencing; peristalsis; vagus nerve; homeostasis; vagal afferents; digestion; mechanoreceptors; motility; mechanosensation; esophagus
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2023.04.025

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders. [Display omitted] •Prox2/Runx3 vagal sensory neurons form intraganglionic laminar endings in the esophagus•Prox2/Runx3 vagal sensory neurons function as mechanoreceptors•Prox2/Runx3 vagal sensory neurons are required for swallowing in freely behaving mice The vagal sensory neurons that monitor esophageal stretch and distension belong to the MM2 and MM8 subtypes of Prox2/Runx3 neurons. These two subtypes are key for swallowing in vivo, as their ablation causes severe esophageal dysmotility. Knowledge about their molecular makeup might help treat esophageal disease.