Growing embryos face a tight squeeze when it's time to pack internal organs. A new study published in Nature Aug. 4 shows how simple mechanical forces between neighboring types of tissue help organs take shape and grow.
The work is among the first to uncover how an embryo develops from groups of cells into distinctly shaped organs. Though the research largely focuses on the mid-gut in chicken embryos, the findings are relevant to other vertebrates and the formation of other organs, including the heart. Such insights into how organs form could aid efforts to diagnose and prevent birth defects and diseases.
The research reveals how a vertebrate digestive system -- a tube up to five times longer than the frame housing it -- fits inside the body by packing itself into an organized bundle of intestinal coils. This formation, the researchers report, hinges on the growth of the dorsal mesentery, a bridge of artery-packed tissue anchoring the gut tube.
"Until now the dorsal mesentery seemed to offer only structural support; no one talked about its possible functions," said developmental biologist Natasza Kurpios, assistant professor of molecular medicine at Cornell's College of Veterinary Medicine and a first author with Thierry Savin and Amy Shyer of Harvard, where Kurpios conducted the study before she came to Cornell in 2009. "In adults, it's a thin piece of tissue suspending the intestines and guiding arteries to them. But in embryos, we found that its properties aid construction by pulling back the gut and forcing it to loop."
Using tiny surgical scissors Kurpios separated the looping gut tube from the dorsal mesentery.
"The gut instantaneously un-looped into a straight tube and the mesentery contracted like a relaxed rubber band," said Kurpios. "Clearly the mesentery was under tension and the gut-mesentery connection had exerted tension on both that affected each other's shape. We measured the organs' growth rates throughout development and found that the gut tube grows far faster than the mesentery: nearly four-fold in chickens. The gut wants to grow, the slower mesentery holds it back, so the gut loops."
At Harvard, Savin built a simple physical model using a latex sheet (to act as the mesentery) stitched to a rubber tube (to act as the intestine) to mimic the mechanical forces that create the gut looping. Experimenting with different physical properties in the two materials, Savin and colleagues developed a formula predicting the looping patterns based on the thickness and elasticity of the latex and the radius of the rubber tube.
Kurpios and her colleagues then applied the model to animals, finding that in chickens, quail, zebra finches and mice the model predicted the patterns and properties correctly. "We've found a simple physical explanation for what had seemed like a complex biological mystery," Kurpios said.
By uncovering the basic mechanisms for how organs form, researchers may now begin to understand such developmental deformations as intestinal malrotation -- which may cause knotting of tissue that blocks circulation -- a birth defect in one in 500 newborns that can lead to death.
With the help of a newly funded grant from the March of Dimes, Kurpios says her Cornell lab is completing new research that identifies a hierarchy of specific genes responsible for gut development. "People have not understood how you can go from groups of cells to the actual shape of organs," she said. "We are now uncovering that link."
Other co-authors include Clifford Tabin and L. Mahadevan, both at Harvard. The research was funded by the National Science Foundation, National Institutes of Health and the MacArthur Foundation.
Carly Hodes is a writer at Cornell's College of Veterinary Medicine.