Genetic Insights Reveal Key Drivers in Formation of the Gut's Nervous System

Recent research conducted by Vanderbilt University scientists, including members from the Vanderbilt Brain Institute, has advanced our understanding of how the enteric nervous system (ENS)—often referred to as the "brain" of the gut—develops and functions. This new study, published in Cellular and Molecular Gastroenterology and Hepatology, sheds light on the genetic mechanisms that guide the formation of gut neurons responsible for gastrointestinal motility, which is crucial for moving food through the digestive tract.

The study was led by principal investigator Michelle Southard-Smith, focusing on the role of the SOX10 protein in early nerve cell development within the gut. The team used genetically engineered mouse models combined with high-resolution, single-cell RNA sequencing to explore the initial stages of neuron formation in the ENS. Their innovative approach allowed them to detect transient transcription factors—proteins that regulate gene expression—that are often overlooked in standard analyses, revealing a greater diversity in developing enteric neurons.

A significant finding of the research was that SOX10, previously thought to be limited to progenitor and glial support cells, is actually present in early-forming neurons, indicating it has a more direct role in neuron development than previously believed. Mutations in the Sox10 gene can disrupt the developmental trajectory of neurons, leading to an imbalance of neuron types that persists after birth, potentially impairing gut motility.

Additionally, the research uncovered an unexpected role for Hox genes, renowned for their function in body patterning. Many Hox genes, including Hoxa6, which had not been previously associated with the ENS, are active during early gut neuron development. The activity of Hoxa6 was found to be linked to Sox10 mutations, implicating it in the formation of specific neuron types.

The researchers aim to pinpoint which Hox genes are directly regulated by Sox10 and to map the gene networks critical for ENS development. Ultimately, this work aims to inform regenerative therapies for gastrointestinal disorders like Hirschsprung disease, irritable bowel syndrome, and chronic constipation. The team envisions that understanding these genetic pathways could lead to the development of neuron transplant therapies to restore normal gut movement.

This groundbreaking study relied heavily on Vanderbilt’s core facilities, including the Cell Imaging and Flow Cytometry Shared Resources, emphasizing the collaborative effort behind this discovery. By illuminating the pivotal genetic drivers of ENS formation, scientists hope to pave the way for future treatments that alleviate gut motility disorders and improve patient quality of life.

Source: https://medicalxpress.com/news/2025-09-uncover-critical-genetic-drivers-gut.html