Prox2 and Runx3 vagal sensory neurons regulate esophageal motility

Elijah D Lowenstein; Pierre-Louis Ruffault; Aristotelis Misios; Kate L Osman; Huimin Li; Rachel S Greenberg; Rebecca Thompson; Kun Song; Stephan Dietrich; Xun Li; Nikita Vladimirov; Andrew Woehler; Jean-François Brunet; Niccolò Zampieri; Ralf Kühn; Stephen D Liberles; Shiqi Jia; Gary R Lewin; Nikolaus Rajewsky; Teresa E Lever; Carmen Birchmeier

doi:10.1016/j.neuron.2023.04.025

Prox2 and Runx3 vagal sensory neurons regulate esophageal motility

Neuron. 2023 Jul 19;111(14):2184-2200.e7. doi: 10.1016/j.neuron.2023.04.025. Epub 2023 May 15.

Authors

Elijah D Lowenstein¹, Pierre-Louis Ruffault², Aristotelis Misios³, Kate L Osman⁴, Huimin Li⁵, Rachel S Greenberg⁶, Rebecca Thompson⁴, Kun Song², Stephan Dietrich⁷, Xun Li⁸, Nikita Vladimirov⁹, Andrew Woehler⁹, Jean-François Brunet¹⁰, Niccolò Zampieri⁷, Ralf Kühn¹¹, Stephen D Liberles⁶, Shiqi Jia⁵, Gary R Lewin¹², Nikolaus Rajewsky¹³, Teresa E Lever⁴, Carmen Birchmeier¹⁴

Affiliations

¹ Developmental Biology/Signal Transduction, Max Delbrück Center for Molecular Medicine, Berlin, Germany; NeuroCure Cluster of Excellence, CharitéUniversitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
² Developmental Biology/Signal Transduction, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
³ Developmental Biology/Signal Transduction, Max Delbrück Center for Molecular Medicine, Berlin, Germany; NeuroCure Cluster of Excellence, CharitéUniversitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁴ Department of Otolaryngology - Head & Neck Surgery, University of Missouri School of Medicine, Columbia, MO, USA.
⁵ The First Affiliated Hospital, Jinan University, Guangzhou, China.
⁶ Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Development and Function of Neural Circuits, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁸ Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁹ Systems Biology Imaging, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
¹⁰ Institut de Biologie de l'ENS (IBENS), Inserm, CNRS, École normale supérieure, PSL Research University, Paris, France.
¹¹ Genome Engineering & Disease Models, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
¹² Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
¹³ Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
¹⁴ Developmental Biology/Signal Transduction, Max Delbrück Center for Molecular Medicine, Berlin, Germany; NeuroCure Cluster of Excellence, CharitéUniversitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Electronic address: [email protected].

PMID: 37192624
DOI: 10.1016/j.neuron.2023.04.025

Abstract

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.

Keywords: digestion; esophagus; homeostasis; mechanoreceptors; mechanosensation; motility; peristalsis; single-cell RNA sequencing; vagal afferents; vagus nerve.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Core Binding Factor Alpha 3 Subunit* / genetics
Core Binding Factor Alpha 3 Subunit* / metabolism
Esophagus* / innervation
Esophagus* / metabolism
Esophagus* / physiology
Gastrointestinal Motility* / genetics
Gastrointestinal Motility* / physiology
Homeodomain Proteins* / genetics
Homeodomain Proteins* / metabolism
Mechanoreceptors / physiology
Mice
Neurons, Afferent / physiology
Sensory Receptor Cells* / metabolism
Sensory Receptor Cells* / physiology
Stomach / innervation
Stomach / metabolism
Stomach / physiology
Vagus Nerve* / physiology

Substances

Core Binding Factor Alpha 3 Subunit
Homeodomain Proteins
Runx3 protein, mouse