NEW YORK, Dec. 16, 2025 /PRNewswire/ -- During development of the digestive system, a complex network of nerves forms around it, creating a "second brain" — the enteric nervous system (ENS) — which controls the movement of food and waste through the gut. But a combination of changes in the molecular letters making up certain genetic instructions can prevent these nerves from developing properly, leading to Hirschsprung disease (HSCR), a painful and often dangerous condition in which babies develop intestinal blockage and are unable to pass stool.
A study led by NYU Langone Health researchers reveals a new strategy to study this disorder in mice that better mimics how the disease manifests in humans. Previous HSCR animal models only looked at the role individual genes played in causing the disease, but the new approach is based on how interactions among multiple genes control the condition.
"We now have a much more realistic and accurate way to model Hirschsprung disease that will help us understand the disease in a way we could not before," said study first author Ryan Fine, PhD, a postdoctoral fellow at the Center for Human Genetics and Genomics at the NYU Grossman School of Medicine. "Our study shows for the first time how some of the most well-known mutations, DNA code changes, in Hirschsprung disease work together to obstruct intestinal nervous system development."
The work was led by Aravinda Chakravarti, PhD, the Muriel G. and George W. Singer Professor of Neuroscience and Physiology in the Department of Neuroscience at the NYU Grossman School of Medicine and director of the Center for Human Genetics and Genomics at the school. Chakravarti has studied HSCR for more than 30 years and helped identify the two main genes associated with HSCR: rearranged during transfection (RET) and endothelial receptor type B (EDNRB).
In previous animal studies of HSCR, researchers "knocked out" either RET or EDNRB, meaning they mutated the gene so that its function was completely destroyed. While this prevented ENS from forming properly and mimicked some aspects of human disease, other HSCR characteristic elements were missing in the mouse models. For example, in humans, the disease is four times more common in males and tends to only affect the colon's lower regions. But in the knockout mice, disease incidence is similar between males and females, and the enteric nervous system is defective throughout the entire colon and small intestine.
Published online Oct. 21 in the journal PNAS, the new study describes how combining weaker mutations in both RET and EDNRB creates a more realistic model of HSCR in mice. Instead of completely knocking out either gene, the researchers made different combinations of mice in which one or both genes were either still partially functional or in which just one copy of the gene was deleted.
In the combination that best replicated the symptoms of human disease, only one copy of RET was knocked out and both copies of EDNRB were partly functional. These mice had normal nervous system development in their small intestines and male mice were more likely to be affected than females.
The researchers then were able to work out the molecular details of how the combined genetic mutations were causing the disease. HSCR is believed to be caused by a total lack of nerve cells in the gut, so the researchers were surprised to find that during development, HSCR mice had plenty of immature neural cells (progenitor cells) in their intestines — in fact, they actually had more than the healthy mice.
To understand what could explain the discrepancy between the plentiful immature ENS cells and complete absence of mature ones, the researchers analyzed which genes were different in the HSCR mice. RET and EDNRB control the activity levels of many different genes, but the researchers found an especially large increase in the levels of SOX2OT, a gene that controls how neural progenitor cells mature and become part of a full-fledged nervous system. This observation led them to speculate that without fully functioning RET and EDNRB to control it, SOX2OT could interfere with how the progenitor cells matured and prevent full ENS development.
Chakravarti says his team plans to use this mouse model to answer other difficult questions about HSCR, but the approach is not limited to this condition. The strategy of studying multiple mutations simultaneously has been used before in cancer studies, he says, but not as much for developmental disorders.
"I think this is a model for many other complex human disorders," said Chakravarti. "By studying complex disease the way it actually occurs in humans — as a result of smaller mutations across multiple genes rather than from the complete loss of a single gene — we can better understand the subtleties of the condition and get closer to life-saving treatments."
Funding for the study was provided by National Institutes of Health grant HD028088.
Other NYU Langone researchers involved in the study are Rebecca Chubaryov, Mingzhou Fu and Gabriel Grullon.
About NYU Langone Health
NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.
Media Inquiries
Shira Polan
212-404-4279
Shira.Polan@NYULangone.org
STUDY LINK:
https://www.pnas.org/doi/10.1073/pnas.2507062122
View original content to download multimedia:https://www.prnewswire.com/news-releases/new-modeling-approach-sheds-light-on-rare-gut-disease-302640037.html
SOURCE NYU Langone Health System
