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Julie Kiefer

Manager, Science Communications, University of Utah Health Sciences Office of Public Affairs
Phone: 801-587-1293

Mar 25, 2015 12:00 PM

Listen to an interview about the research on The Scope Radio.

(Salt Lake City) – Congenital diaphragmatic hernia (CDH) is not as well known as muscular dystrophy and cystic fibrosis, but like them it is a life-threatening birth defect, and is just as common. Occurring in one in 2,500 births, CDH causes the guts and liver to protrude through a defective diaphragm and into the chest cavity, where they interfere with the lungs.

Although many genetic mutations have been linked to CDH, a new study from the University of Utah School of Medicine is the first to demonstrate a linkage between genetic variation and a physiological mechanism that gives rise to defects in the diaphragm. The research points to a crucial role for connective tissue in CDH, and in guiding normal development of the diaphragm. These findings are published in Nature Genetics.

Research like this could tell physicians when and how CDH occurs in fetal development, opening the  door to preventative treatments. “We learned that these defects happen really early – much earlier than previously thought,” says Gabrielle Kardon, Ph.D., associate professor of human genetics and principal investigator on the study.  She stressed there are currently no therapeutic interventions to prevent CDH, and even with surgical patching of the diaphragms CDH is “silently killing half of the affected babies” – referring to the 50 percent mortality rate with this condition. Her lab is poised to test whether drugs can prevent the birth defect in animal models.

The study began with a developmental question: how is the diaphragm built as the embryo grows? The diaphragm is the only essential skeletal muscle. It is necessary for breathing and acts as a barrier that separates the liver and guts from the heart and lungs. While it’s known that the mature diaphragm is composed of a domed muscle surrounded by connective tissue that attaches to tendons and bones, how the diaphragm develops has been a mystery. The researchers genetically tagged different cell populations in mice, a technique used to visualize how the cells come together to make the diaphragm. Surprisingly, they found that the connective tissue cells are key: they send molecular signals that tell the muscle cells how to assemble properly.

If connective tissue is important for the normal development of the diaphragm, it might also be involved in CDH. “We have lots of data suggesting that CDH is due to genetic mutations,” says Kardon. “But there's no line connecting the genetic mutation to the diaphragm defect.” The team saw that in mice, the diaphragm’s connective tissue cells expressed a gene, Gata4.  Mutations in this same gene have been strongly correlated with CDH in humans. This suggested that genetic defects within connective tissue might be a cause of CDH.

They tested their hypothesis by silencing the Gata4 gene in the connective tissue cells and observing how this affected development. In every case in which the Gata4 gene was “knocked out,” the mouse developed a hernia in its diaphragm.

But how does the hernia form? Surprisingly, the hernias did not develop from a hole in the diaphragm, as was assumed. Without Gata4 in the connective tissue, muscle develops incompletely – creating a localized region made entirely of connective tissue. As the growing liver presses on this weak spot, the diaphragm eventually gives way and the liver bulges through.

Their genetic studies, aided by computer models made in collaboration with bioengineers, show that CDH only develops when a weaker region of connective tissue is surrounded by stronger muscular tissue; counterintuitively, diaphragms made entirely of connective tissue did not develop hernias. These results show that small defects in muscle development lead to hernias, potentially making fixing the underlying problem more approachable. “Using our animal model of CDH, we are now in an excellent position to test therapies and provide hope for CDH patients,” says Kardon.

The diaphragm is not only crucial for the survival of mammals, but unique to them as well. This presents an interesting evolutionary problem. “You look at our nearest ancestors and there's nothing,” Kardon says. “How do you have a major structure, which we are completely dependent upon, appearing very quickly and completely whole?” All mammals have fully-formed muscular diaphragms, whereas our most-recent ancestors (birds and reptiles) have only a septum made from connective tissue. Because this research suggests any transitional structure between these two states would be prone to deadly hernias, it provides evidence of the rapid evolutionary development of the diaphragm.

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This work was made possible by the University of Utah, March of Dimes, and National Institute of Child Health and Development, NIH.

Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. A. Merrell, B. Ellis, Z. Fox, J. Lawson, J. Weiss, G. Kardon, Nature Genetics March 25, 2015

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Model of herniation showing that thinner, weaker regions with connective tissue but no muscle herniate in response to pressure of growing, underlying liver

Structure of the embryonic mouse diaphragm with muscle in red, tendon in green, and nerves in blue.

Model of Herniation in Congenital Diaphragmatic Hernia (CDH)

CDH is a common defect that occurs in 1 in 2,500 births, and 50 percent patients die from related complications. Research from the University of Utah provides new information on how CDH arises, opening avenues for researching therapeutic interventions. 

CDH model
LEFT - The diaphragm acts as a barrier that separates the liver and guts in the abdominal cavity from the heart and lungs in the chest cavity. A normal, healthy diaphragm is comprised of a dome-shaped layer of muscle (red) that overlies a layer of connective tissue (green, not visible on left). CENTER – Experiments in mice show that diaphragms missing muscle do not develop hernias. RIGHT – Research suggests that CDH originates from regions with connective tissue but no diaphragm muscle. Internal pressure from growing organs in the abdominal cavity causes them to protrude through the weak spots and into the chest cavity.

Additional Resources

birth defect congenital diaphragmatic hernia