Scientists at Weill Cornell Medical College used genetic methods to successfully repair cleft lips in mice embryos specially engineered for the study of cleft lip and cleft palate. The research breakthrough may show the way to prevent or treat the conditions in humans.
Cleft lip and cleft palate are among the most common birth defects, with treatment requiring multiple cycles of surgery, speech therapy and orthodontics. To date, there have been very few pre-clinical methods that allow researchers to study the molecular causes of these malformations. In particular, there has been a lack of animal models that accurately reflect the contribution of multiple genes to these congenital deformities in humans.
In a report in a recent issue of the journal Developmental Cell, Dr. Licia Selleri, associate professor of cell and developmental biology at Weill Cornell Medical College, and her co-authors report the first multigenic mouse model of cleft lip with or without cleft palate. The researchers uncovered the role of genes for Pbx (Pre-B Cell Leukemia Transcription Factor) proteins in coordinating cellular signaling behaviors crucial for the development of these abnormalities. They also discovered that altering one type of molecule within the Wnt signaling pathway (that comprises a network of proteins best known for their roles in embryogenesis) is sufficient to correct the defects.
Dr. Selleri has studied Pbx proteins for many years and has previously demonstrated their involvement in organ and skeletal development. In her latest study, she and her collaborators, including postdoctoral fellows Drs. Elisabetta Ferretti and Bingsi Li, tested whether these proteins also play a role in facial development by using mutant mice that lacked various combinations of three Pbx genes in the ectoderm, the embryonic cell layer that gives rise to the lip and nose.
The researchers found that only mutations affecting multiple Pbx genes resulted in complete cleft lip, with or without cleft palate, in all of the mouse embryos with these compound mutations. This finding differs from those of previous studies using other mammal models of these conditions, in which a mutation in a single gene produced defects in only some of the animals, Dr. Selleri says. The role of Pbx genes in the development of the shape of the face is a new and surprising finding, she adds.
Moreover, the mouse embryos with multiple Pbx mutations also had reduced or absent Wnt activity, which plays a prominent role in embryo development, within the ectoderm. Dr. Ferretti, the first author of this study, found that Pbx genes regulate a chain of signaling molecules implicated in cleft lip with or without cleft palate, including Wnt, fibroblast growth factors (FGFs), p63, and interferon regulatory factor 6 (Irf6) -- signaling pathways that exist across mammal species. Disturbances in this network lead to a decrease in programmed cell death, thereby interfering with the proper fusion of facial tissues and resulting in cleft lip.
When Dr. Li, the second author of this study, used genetic methods to restore Wnt activity in the ectoderm of mouse embryos with compound Pbx mutations, the cleft lips in all of these animals completely disappeared. "To my knowledge, this is the first time that anyone has corrected this defect in embryos, and we really show here that Wnt is a critical factor," Dr. Selleri says. "This is a very provocative result because it opens a completely new avenue of strategies for tissue repair."
To follow up on this work, Dr. Selleri plans to test whether supplying Wnt molecules to Pbx-mutated mouse embryos placed within an environment that mimics the uterus is sufficient to correct or even prevent the abnormalities. Compared with genetic manipulations, this approach of delivering Wnt signals directly to the uterus would be more realistic for implementation in humans, Dr. Selleri says. She has just initiated a collaboration with Jason Spector, assistant professor of plastic surgery at Weill Cornell Medical College and with Larry Bonassar, associate professor of biomedical engineering at Cornell University, to envision Wnt-related strategies for tissue repair, such as tissue implants that would deliver Wnt molecules to correct these defects either in utero before the birth of the fetus, or after birth without the need of many surgeries.
Additional study collaborators include Rediet Zewdu and Victoria Wells of Weill Cornell Medical College; Jean M. Hebert of Albert Einstein College of Medicine in the Bronx, N.Y.; Courtney Karner of the University of Texas, Southwestern Medical Center, in Dallas, Texas; Matthew J. Anderson of the National Cancer Institute in Frederick, Md.; Trevor Williams of the University of Colorado, Denver; Jill Dixon and Michael J. Dixon of the University of Manchester in the U.K.; and Michael J. Depew of King's College London in the U.K.
The research was supported by a Marie Curie Fellowship, the Medical Research Council in the U.K., the Royal Society, King's College London, March of Dimes and Birth Defects Foundation, the National Institutes of Health, the Cleft Palate Foundation, and the Alice Bohmfalk Trust.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.
Takla Boujaoude | EurekAlert!
Algae-killing viruses spur nutrient recycling in oceans
18.07.2019 | Rutgers University
How are pollen distributed in the air?
18.07.2019 | Leibniz-Institut für Troposphärenforschung e. V.
Scientists have visualised the electronic structure in a microelectronic device for the first time, opening up opportunities for finely-tuned high performance electronic devices.
Physicists from the University of Warwick and the University of Washington have developed a technique to measure the energy and momentum of electrons in...
Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.
Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...
For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.
Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...
An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".
The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...
An interdisciplinary research team at the Technical University of Munich (TUM) has built platinum nanoparticles for catalysis in fuel cells: The new size-optimized catalysts are twice as good as the best process commercially available today.
Fuel cells may well replace batteries as the power source for electric cars. They consume hydrogen, a gas which could be produced for example using surplus...
24.06.2019 | Event News
29.04.2019 | Event News
17.04.2019 | Event News
18.07.2019 | Health and Medicine
18.07.2019 | Life Sciences
18.07.2019 | Health and Medicine