Summary: Researchers used single-cell methods to map the neuron types of the enteric nervous system in mice and traced how these cells diversify during fetal development. Their results reveal that enteric neuron formation follows distinct principles from brain neuron development.
Source: Karolinska Institutet
Researchers at Karolinska Institutet have produced a detailed molecular map of the enteric nervous system (ENS) in the mouse intestine and identified how different enteric neuron types emerge during embryonic development. The study, published in Nature Neuroscience, distinguishes multiple neuron classes in the myenteric plexus and uncovers a novel pattern of neuronal diversification that contrasts with central nervous system development.
The human gastrointestinal tract contains its own extensive nervous system that controls gut motility, fluid balance, blood flow and communicates with immune cells and the microbiome. Often referred to as the “second brain,” the ENS operates largely autonomously and influences overall health. Disorders of gut function affect a large portion of the population and are linked to chronic gastrointestinal symptoms and a variety of systemic conditions.
Using single-cell RNA sequencing, which profiles gene expression in individual cells, the research team mapped the cellular composition of the myenteric plexus in the mouse small intestine. They classified enteric neurons according to their molecular signatures and identified twelve distinct neuron classes. These include multiple subtypes of sensory neurons—some primarily responsive to chemical signals in the gut and connected to immune interactions, others more sensitive to mechanical stimuli—as well as motor neurons and interneurons that coordinate intestinal activity.
Beyond cataloguing neuron classes, the study investigated how the ENS forms during gestation. Unlike many regions of the central nervous system, where stem or progenitor cells are regionally pre-programmed to produce particular neuronal types, the enteric nervous system must generate a consistent set of neuron types along the entire length of the gut. The authors show that, in the ENS, many neuron identities arise after cells exit the cell cycle—that is, postmitotically—rather than being determined while still dividing. The team describes a binary neurogenic branching event that generates two neuron classes early on, followed by further postmitotic diversification that produces the remaining neuron types.
At the molecular level, the study identifies transcriptional regulators associated with class-specific identities and highlights the transcription factor Pbx3 as a contributor to a postmitotic fate transition. Functional experiments link Pbx3 activity to particular differentiation paths, suggesting it plays a key role in shaping enteric neuron diversity.
“Our next step is to activate these defined enteric neuron classes in mice to determine how each cell type contributes to gut physiology,” says Ulrika Marklund, senior author and researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “By coupling targeted manipulation with the molecular taxonomy, we aim to map specific neuronal functions and how they are altered in intestinal disease.”
Marklund adds that the developmental insights could improve strategies for generating particular enteric neuron types from stem cells. Such directed differentiation would be a prerequisite for future cell-based therapies aimed at restoring ENS function in disorders where enteric neurons are lost or dysfunctional, though clinical translation remains a long-term prospect.
Funding: The research received support from several funders, including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Society of Medicine, the Ruth and Richard Julin Foundation, the Ollie and Elof Ericsson Foundation, the Magnus Bergvall Foundation, the Swedish Brain Foundation and the Åke Wiberg Foundation.
About this neurodevelopment research news
Source: Karolinska Institutet
Contact: Press Office, Karolinska Institutet
Image: The image is in the public domain
Abstract
Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing
Autonomous regulation of intestinal function depends on distinct classes of enteric neurons, but the full range of enteric neuron types and their developmental origins have been unclear. Using single-cell RNA sequencing of the mouse small intestine myenteric plexus, this study defines a molecular taxonomy of twelve enteric neuron classes, characterizes markers and cell–cell communication features for motor neurons, sensory neurons and interneurons, and provides tools for class-specific targeting. Transcriptome analysis during embryonic development reveals a differentiation strategy in which two neuron classes arise from a binary neurogenic branching event, while the remaining classes emerge through subsequent postmitotic differentiation. The work identifies both generic and class-specific transcriptional regulators and connects the transcription factor Pbx3 to a postmitotic fate transition. These results create a conceptual and molecular resource for dissecting enteric circuits and for guiding directed differentiation of distinct enteric neuron classes.