Intestinal stability: gut coils hold secrets of organ formation

Our guts, and all of our organs, are arranged in asymmetric patterns from left to right inside our bodies, so that everything can fit in.

At the same time, the development of organs such as the intestine is anything but random. In healthy fetuses, intestinal rotation during development always occurs in a counterclockwise direction and is perfectly timed. It’s a complex process that scientists have long worked to understand.

Chicken embryo intestinal tube where mechanical cues drive gene expression and gut patterning to prevent lethal obstructions.

Currently, Study published on September 23 In Science, it was found that gut turnover during development is regulated by two waves of expression of a transcription factor called Pitx2. It turns out that the second wave is triggered by mechanical signals inside the elastic tissue that stabilizes the intestinal tube, and later becomes a conduit for blood and lymphatic vessels that feed the intestinal tube.

The findings have important implications for understanding the underlying mechanisms of how organs form, which could aid efforts to diagnose and prevent birth defects, such as intestinal malrotation and torsion, in which the developing intestine becomes twisted and stifles itself.

“The entire digestive system is a single tube that absorbs it all of our nutrients, and they are gigantic, so they have to rotate to fit inside our bodies” Natasha CorbiusD., assistant professor of molecular medicine in the College of Veterinary Medicine and senior author of the study. Bhargav D. Sanketi, a doctoral student in the Corbius laboratory, is the paper’s first author.

“What we’ve found for years is that the rings are highly conserved and they’re very structured,” Corbius said.

It turns out that such organs as the heart, liver, lungs, intestines (intestines) are all in an asymmetric position – they are located on one side of the body, or extend to the left and right, but not in the middle. Understanding how the gut is formed with left-right asymmetry can reveal patterns of development found in other organs, such as the heart.

Previous work has shown that a gene called Nodal induces the first wave of Pitx2 to create the early body plan. But the presence of Nodal is short-lived, and once it stimulates Pitx2 expression, it disappears before intestinal turnover occurs. Therefore, it was not known for a long time how Pitx2 remains active to direct gut turnover when Nodal is gone. “Our first surprise was that the Pitx2 expression actually disappears and then comes back again because the gut tube is ready to rotate,” Corbius said. “So the question was, What awakens Pitx2?”

The researchers found that the sensor, TGF-beta, is dormant until activated by mechanical forces. In the case of the gut, this is dictated by the dorsal mesentery which is attached to the gut tube and held in place. To direct the rotation, the tissues of the dorsal mesentery are significantly stretched on the right side and compressed on the left. When it does, TGF-beta senses these altered forces and activates expression of the second wave of Pitx2, which stimulates gut tube loops. In other words, The Pitx2 wave that creates the asymmetry of the body is different from the wave that circulates in the gut.

In the study, the researchers used mice and engineered chicken embryos, allowing Corbius and his colleagues to open a small window in the egg shell so they could see development and manipulate gene expression.

The lab of co-author Jan Lammerding, a professor in the Mennage School of Biomedical Engineering, used a probe in live embryos to measure stiffness and flexibility in the dorsal mesentery. Measurements revealed right-sided and TGF-beta-Pitx2-induced inhibition of this left-sided stretch, creating an optimal amount of tilt in the tissue for proper gut tube loops.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. March of Dimes; National Heart, Lung, and Blood Institute; Volkswagen Foundation and Cornell Center for Vertebrate Genomics.