The Transcriptomic Landscape and Developmental Blueprint of Submucosal Neurons in the Mouse Small Intestine

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Friday, 29 May 2025

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This study shows the complex neuronal makeup of the enteric submucosal plexus in the mouse small intestine. Researchers have identified two secretomotor neuron types and a new intrinsic primary afferent neuron class using single-cell RNA sequencing and viral labeling. They found these neurons form interconnected networks and closely associate with enterochromaffin cells. Developmental analysis showed these neurons arise from a binary fate decision followed by specialization, similar to the myenteric plexus. The work provides a unified model for neuron development in the gut and offers detailed molecular and morphological insights into submucosal neurons, advancing understanding of gut physiology and neural circuits.

Journal: Nature

Research: Link

Organisation:

Karolinska Institutet, Sweden

Mayo Clinic, USA

RIKEN Center for Integrative Medical Sciences, Japan

Funding:

Swedish Research Council

National Institutes of Health (NIH), USA

Knut and Alice Wallenberg Foundation

Karolinska Institutet

RIKEN Institute of Japan

PUBLIC RELEASE

Provided By: Karolinska Institute

The Transcriptomic Landscape and Developmental Blueprint of Submucosal Neurons in the Mouse Small Intestine

The enteric nervous system (ENS), known as the “second brain,” controls intestinal function independently from the central nervous system. While myenteric neurons are well-studied for their role in gut motility, submucosal neurons which regulate secretion, blood flow, and epithelial interactions—have been less understood at the molecular and developmental level. This study, published in Nature Neuroscience, uses single-cell transcriptomics and lineage tracing to reveal the detailed biology of submucosal neurons.

Three Cardinal Neuronal Classes Identified:

• smENC1: Intrinsic primary afferent neurons (IPANs) with sensory roles, expressing markers like Nmu, Adgrg6, Calcb.
• smENC2: Cholinergic secretomotor neurons expressing Sst, Tac1, Calcb.
• smENC3: Noncholinergic neurons with vasodilatory/secretomotor functions expressing Vip, Npy, Th/Dbh.  

Developmental Trajectories:Two major developmental branches produce these classes, with smENC3 arising from early NOS1 expressing cells and smENC1/smENC2 from NDUFA4L2 and Casz1 expressing precursors, mirroring myenteric neuron maturation.Morphology & Connectivity:Distinct morphologies correspond to functional roles, with complex synaptic cross-talk and unexpected sensory connections to enterochromaffin (5-HT+) cells, redefining submucosal sensory feedback models.Neurovascular Interactions:Minimal direct vascular innervation suggests neurovascular control is indirect or mediated by other cell types.

This study provides a foundational atlas for enteric neuroscience, advancing understanding of gut-brain communication and gastrointestinal diseases.

Attachments:

THE RESEARCH PUBLISHED IN: Nature Neuroscience

{The Transcriptomes, Connections and Development of Submucosal Neuron Classes in the Mouse Small Intestine}