Unraveling the mysteries of Hirschsprung disease, a painful condition affecting newborns, has taken a significant step forward thanks to a groundbreaking study by NYU Langone Health researchers. The key to understanding this disease lies in the intricate dance of multiple genes.
Our digestive system, a marvel of nature, is controlled by a 'second brain' - the enteric nervous system (ENS) - which ensures the smooth passage of food and waste. However, certain genetic changes can disrupt this delicate process, leading to Hirschsprung disease (HSCR). Babies with HSCR suffer from intestinal blockages and an inability to pass stool, making it a critical health concern.
But here's where it gets controversial... Previous animal models focused on individual genes, but this new approach reveals a more holistic view. Dr. Ryan Fine, the study's first author, emphasizes, "Our study shows how some of the most well-known mutations in Hirschsprung disease work together to obstruct intestinal nervous system development."
Led by Dr. Aravinda Chakravarti, a renowned professor and director at NYU Grossman School of Medicine, the study delves into the complex world of HSCR genetics. Chakravarti, with over 30 years of experience studying HSCR, has identified the two main genes associated with the disease: RET and EDNRB.
Previous animal studies, however, had limitations. Researchers would 'knock out' either RET or EDNRB, completely disabling their function. While this mimicked some aspects of the disease, it failed to capture the full spectrum of HSCR characteristics seen in humans. For instance, HSCR is four times more common in males and typically affects the lower regions of the colon, a pattern not reflected in previous mouse models.
Published in the journal PNAS, the new study describes a more realistic HSCR mouse model. By combining weaker mutations in both RET and EDNRB, the researchers created a scenario that better mimics the human condition. Instead of complete gene knockout, they crafted different combinations where one or both genes were partially functional or where only one copy of the gene was deleted.
And this is the part most people miss... In the combination that most closely replicated human symptoms, only one copy of RET was knocked out, while both copies of EDNRB were partly functional. Interestingly, these mice showed normal nervous system development in their small intestines, and male mice were more likely to be affected, mirroring the human disease pattern.
The researchers then delved into the molecular intricacies, uncovering a surprising finding. HSCR is believed to be caused by a total lack of nerve cells in the gut, but the HSCR mice had an abundance of immature neural cells (progenitor cells) in their intestines. To explain this discrepancy, the researchers analyzed the genes of the HSCR mice and found an increase in the levels of SOX2OT, a gene that controls neural progenitor cell maturation. This led them to speculate that SOX2OT, uncontrolled by fully functional RET and EDNRB, could interfere with cell maturation, preventing full ENS development.
Chakravarti's team plans to use this mouse model to explore other HSCR mysteries, but the implications extend beyond this condition. The strategy of studying multiple mutations simultaneously has been applied in cancer research, but less so in developmental disorders. Chakravarti believes, "This is a model for many other complex human disorders. By studying complex disease as it occurs in humans, we can better understand the subtleties and move closer to life-saving treatments."
The study was funded by National Institutes of Health grant HD028088, and other NYU Langone researchers involved include Rebecca Chubaryov, Mingzhou Fu, and Gabriel Grullon.
