Researchers at NYU Langone Health have developed a new way to study Hirschsprung disease (HSCR) in mice that better reflects how the condition appears in humans. HSCR is a rare disorder caused by improper development of the enteric nervous system (ENS), which can lead to intestinal blockages in newborns.
Previous animal models for HSCR focused on disabling individual genes, specifically RET or EDNRB, to mimic the disease. However, these models did not capture key features seen in human patients. For example, while HSCR is more common in males and usually affects only the lower colon in humans, earlier mouse models showed similar rates between male and female mice and affected both the colon and small intestine.
The research team led by Aravinda Chakravarti, PhD, at NYU Grossman School of Medicine, created new mouse models by introducing weaker mutations into both RET and EDNRB genes instead of completely deactivating them. This approach resulted in mice with symptoms closer to those found in people with HSCR—males were more often affected than females, and only specific regions of the gut were involved.
“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 Ryan Fine, PhD, first author of the study and postdoctoral fellow at NYU’s Center for Human Genetics and Genomics. “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 findings were published online October 21 in PNAS.
Dr. Chakravarti explained that their analysis revealed an unexpected result: although HSCR mice had many immature neural progenitor cells during development—more than healthy controls—they still lacked mature nerve cells needed for proper gut function. Further investigation pointed to increased activity of SOX2OT, a gene influencing maturation of neural progenitors. The researchers suggest that disruptions caused by partial loss of RET and EDNRB may allow SOX2OT levels to interfere with normal ENS formation.
“I think this is a model for many other complex human disorders,” said Dr. 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 was provided by National Institutes of Health grant HD028088. Other contributors from NYU Langone included Rebecca Chubaryov, Mingzhou Fu, and Gabriel Grullon.
