Their latest findings, published online Oct. 15 in Nature Genetics, reveal an unexpected role for IRF6 in the growth and development of skin cells, a discovery that may have implications for wound healing and cancer research.
In 2002, Brian Schutte, Ph.D., UI associate professor of pediatrics and nursing, and Jeff Murray, M.D., UI professor of pediatrics, pediatric dentistry and biological sciences, and the Roy J. Carver Chair in Perinatal Health, led a study showing that mutations in IRF6 cause Van der Woude syndrome (VWS), a rare, dominantly inherited form of cleft lip and palate. Subsequently, the researchers found that this gene also is mutated in 10 to 15 percent of the more common, so-called non-syndromic cases of cleft lip and palate. Cleft lip and palate, where the lip or both the lip and palate (roof of the mouth) fail to close, occurs in approximately one of every 1,000 babies.
In order to determine the function of this gene, the researchers created mice that lacked IRF6. These mice had very abnormal skin as well as a cleft palate. Detailed analysis of the mice revealed that IRF6 regulates the proliferation and differentiation of keratinocytes -- the main cell type in the epidermis or outer layer of skin. Keratinocytes also provide a protective barrier around the mouth, gut, liver, lung, kidney and other internal organs.
"This study really looks at the role of IRF6 in skin development. By focusing on skin we felt we could learn more about this specific cell type that is also abnormal in the palate," Schutte said. "The insight we gained into the function of IRF6 will help focus research efforts to identify other genes involved in cleft lip and palate."
Skin is an extremely important tissue, as it is the largest tissue in the body and it provides a critical external barrier. Normal epidermis has four layers of keratinocytes. The UI study showed that mice that lack IRF6 have abnormal skin development and are missing the upper two cellular layers of the epidermis. The researchers also showed abnormal proliferation of keratinocytes in one of the remaining two layers and failure of these cells to die off or differentiate as normal.
Although humans with Van der Woude syndrome do not have skin defects, a similar human condition, called popliteal ptyergium syndrome (PPS) that is also caused by mutations in IRF6, does cause skin abnormalities in addition to cleft lip and palate. Thus, the UI researchers were not completely surprised by the skin abnormalities in the mice.
Mice provided a particularly good animal model for the UI study because mice and humans have very similar facial development and both share the distinctive mammalian structure of a palate, which separates the nasal airway from the mouth allowing a baby to suckle. In addition, it is fairly easy to create mutations in mice to study a particular gene's function.
"Having an animal model for a major human birth defect like cleft lip and palate provides us with the opportunity to investigate ways to better treat and prevent these disorders much more quickly than was previously possible," Murray said. "Dr. Schutte's work has also expanded our knowledge of other critical areas of human health such as the role of our skin in development and in how wounds and scars may heal."
"Our results open many new avenues of research because the function we discovered for IRF6 is vastly different than the best understood function for the other IRF genes," Schutte added.
IRF6 belongs to a family of nine IRF genes, which have been extensively investigated. The UI study reveals that IRF6 has a different function than the other known IRF genes, which are all primarily involved in the immune response. Its newly identified role in cell proliferation and differentiation may mean that IRF6 also is involved in other medically important areas of biology such as cancer and wound healing.
The main funding for the study is from a National Institute of Dental and Craniofacial Research grant for the UI Craniofacial Anomalies Research Center (CARC). Murray is the principal investigator for the grant. The CARC also supported a complementary study by researchers at the University of Manchester in England, who are collaborating with Schutte and Murray. The Manchester team investigated a different mutation in the mouse IRF6 gene and observed similar results to the UI study. This second study will also be published in Nature Genetics.
"The support from the CARC was critical to the completion of these two studies because several different disciplines were needed to characterize the abnormalities of the mice," Schutte said. "The CARC brought together specialists to attack the problem from many different directions."
Dave Pedersen | EurekAlert!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research