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Figure 2: Deletion of Gata4 produces localized amuscular regions weaker than nearby muscular regions resulting in CDH. Image Credit: Nature Genetics

About Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is not as well known as muscular dystrophy and cystic fibrosis, but is also a life-threatening birth defect — and just as common.

Occurring in one in 3,000 births, CDH allows the intestines and liver to protrude through a defect in the diaphragm and into the chest cavity to push against the heart and 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 link between gene variation and a physiologic mechanism that allows for defects to occur in the diaphragm. The research points to the crucial role of connective tissue in CDH, and in how to guide normal development of the diaphragm. The findings were published March 25, 2015 in Nature Genetics.

Research like this could tell us how and when CDH occurs in the fetus, opening the door for preventative treatments.

"We learned that these defects happen really early - much earlier than previously thought, silently killing half of affected babies."

Gabrielle Kardon PhD, Associate Professor of Human Genetics, The University of Utah School of Medicine, and principal investigator of the study.

Kardon stressed there are currently no therapeutic interventions to prevent CDH, and even with surgical patching of the diaphragms CDH has a 50 percent mortality rate. Her lab is now poised to test whether drugs can prevent the birth defect in animal models.

The study began with the developmental question: how is the diaphragm built as the embryo grows? The diaphragm is our only essential skeletal muscle as it is needed for breathing while also separating the liver and intestines from the heart and lungs. It is known that a mature diaphragm is composed of domed muscle surrounded by connective tissue attached to tendons and bones. How it develops has been the mystery.

Researchers genetically tagged each different cell populations in mice in order to visualize how cells organize to make the diaphragm. Surprisingly, they found that connective tissue cells are key as these send molecular signals to tell muscle cells how to assemble properly.

If connective tissue is important for the normal development of the diaphragm, it therefore might also be involved in CDH. Kardon: "We have lots of data suggesting that CDH is due to genetic mutations. But there's no line connecting genetic mutation to diaphragm defect." However, the scientists saw that in mice, the diaphragm's connective tissue cells expressed the gene Gata4, and mutations in Gata4 have been strongly correlated with CDH in humans. This suggested that genetic defects within connective tissue might be a cause of CDH.

To test this hypothesis, the scientists silenced the Gata4 gene in connective tissue cells and observed how this affected that tissue's development. In every case where Gata4 was "knocked out" (or "turned off") the mouse developed a hernia in its diaphragm.

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

Aided by computer models made with the help of bioengineers, genetic studies show that CDH only develops when a weak region of connective tissue is surrounded by stronger muscular tissue; diaphragms made entirely of connective tissue did not develop hernias. So, these results demonstrate that small defects in muscle development are what really lead to hernias. This information, identifying a loss of Gata4 leading to small muscle defects, could potentially make attempting to fix the underlying problem of CDH possible.

"Using our animal model of CDH, we are now in an excellent position to test therapies and provide hope for CDH patients."

Gabrielle Kardon PhD

Abstract
The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH.

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

Listen to the podcasts below for more information on congenital diaphragmatic hernia:

An Unborn Baby with CDH: "The Lonliest Diagnosis"

Congenital Diaphragmatic Hernia: Your Questions Answered

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

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