How Genetics and Physics Interact To Form the Gut

One paper, in Developmental Cell, shows how a set of well-known developmental instructions called Hox genes dictate gut formation.

The second paper, in Proceedings of the National Academy of Sciences (PNAS), shows how geometry, elastic properties, and growth rates control various mechanical patterns in different parts of the gut.

Building on a history of Hox

For the Developmental Cell study, first author Hasreet Gill, then a PhD student in the Harvard Kenneth C. Griffin Graduate School of Arts and Sciences, and colleagues traced the gut development of a chicken embryo as a model organism.

“I wanted to understand why different regions in the intestine, from the anterior, meaning esophagus, to the posterior, meaning large intestine, end up with different shapes,” she said.

The study built on previous work looking at how Hox genes are involved in organ differentiation. These genes have been highly conserved throughout animal evolutionary history and are found in chickens, humans, and all other vertebrates. Scientists were awarded the Nobel Prize in 1995 for revealing the role of Hox genes in differentiating the various segments of the fruit fly body.

It has long been known that Hox genes are the instructions that lay the groundwork for how different organs, including the gut, are sectioned off and shaped. But the detailed “how” of this process was a mystery.

Gill and colleagues set out to solve it.

The team included Gill’s PhD advisor, Clifford Tabin, the George Jacob and Jacqueline Hazel Leder Professor of Genetics and head of the Department of Genetics in the Blavatnik Institute at Harvard Medical School, who specializes in studying the influence of genetics on the form and structure of animals during development and evolution.

It also included long-standing Tabin Lab collaborator L. Mahadevan, professor in applied mathematics, physics, and biology in Harvard’s John A. Paulson School of Engineering and Applied Sciences and Faculty of Arts and Sciences. Mahadevan Lab members such as then-postdoctoral fellow Sifan Yin offered expertise in theoretical and computational analysis to define how physical forces influence organ shape.

Different properties in the large and small intestine

The project involved revisiting a 1990s-era experiment in which Tabin Lab members expressed a particular Hox gene in a small intestine and found that that intestine took on the characteristics of a large intestine.

In the new work, Gill repeated the experiment while probing the mechanical characteristics of the different parts of the gut in chick embryos, with careful consideration for things like wall stiffness, rate of growth, and thickness of tissue.

Gill and colleagues found measurable differences in the mechanical properties of the tissues that make up the large and small intestines. They then showed that these properties are directly involved in how gut tissues arrive at their final shapes.

For example, Gill found that the tissues that form villi in the small intestine have different stiffness parameters than those that shape the inside walls of the large intestine, which form larger, flatter, more superficial folds.

The team further found that the HoxD13 gene in particular regulates the mechanical properties and growth rates of the tissues that eventually lead to the large intestine’s final shape. Other, related Hox genes may define those same properties for the small intestine.

The researchers also illuminated the role of a downstream signaling pathway called TGF beta, which is controlled by Hox genes. By tuning the amount of TGF beta signaling in the chick embryos, the team found they could switch the shapes of the different gut regions.

Seeing the importance of this pathway, long ago implicated in conditions involving fibrosis (tissue thickening and scarring), was an important basic-science step toward fully understanding gut development in vertebrates.

The insights could also lead to new insights into colon cancer and other fibrotic diseases of the gut, Gill said.

“One possibility is that the disease is co-opting a developmental program that can cause an excessive deposition of extracellular matrix, and this ends up being harmful to the patient,” she said.

“Having this developmental context, especially related to Hox gene expression, might prove useful at least for understanding the broader context of why these diseases are happening in people.”

The forces that shape us

The complementary PNAS paper, co-led by Gill and Yin, focused on how mechanical and geometric properties directly affect the structures, shapes, and sizes, or morphologies, of tissues.

Of particular interest were “more complicated, secondary buckling patterns, like period-doubling and multiscale creasing-wrinkling patterns,” said Yin, an expert in theoretical modeling and numerical simulations of active and growing soft tissues.

The results contribute to a body of work that is allowing scientists to begin probing aspects of the plasticity of gut development, especially in an evolutionary context, Mahadevan said.

“Could it be that natural variations in the genetic signals lead to the variety of functional gut morphologies that are seen across species?” he asked. “And might these signals be themselves a function of environmental variables, such as the diet of an organism?”

Yin said the two papers provide a new paradigm for studying how genes affect the development of shape, also known as morphogenesis.

“Morphogenesis is driven by forces arising from cellular events, tissue dynamics, and interactions with the environment,” Yin said. “Our studies bridge the gap between molecular biology and mechanical processes.”

Adapted from an article in the Harvard Gazette.