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Breakthrough in Cleft Research

A mouse model could show the way to new treatments and prevention strategies.

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Scientists at Weill Cornell Medical College, in New York, used genetic methods to repair cleft lips successfully in mice embryos specially engineered for the study of cleft lip and palate [Developmental Cell, 21 (4): 627-41]. The research breakthrough may show the way to new treatments and prevention strategies in humans.

Cleft lip and 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.

Licia Selleri, MD, PhD, associate professor of cell and developmental biology, and co-authors have reported the first multigenic mouse model of cleft lip with or without cleft palate. They 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 is sufficient to correct the defects.

Dr. Selleri previously demonstrated the involvement of Pbx proteins in organ and skeletal development. In the current study she and her collaborators, including postdoctoral fellows Elisabetta Ferretti, PhD, and Bingsi Li, PhD, 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.

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, the researchers found. 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. The role of Pbx genes in the development of the shape of the face is a new and surprising finding, Dr. Selleri said.

Moreover, the mouse embryos with multiple Pbx mutations had reduced or absent Wnt activity, which plays a prominent role in embryo development, within the ectoderm. Dr. Ferretti, the first author of the 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, used genetic methods to restore Wnt activity in the ectoderm of mouse embryos with compound Pbx mutations, the cleft lips in the animals disappeared completely.

"To my knowledge, this is the first time that anyone has corrected this defect in embryos, and we show that Wnt is a critical factor," Dr. Selleri stated. "This is a very provocative result because it opens a completely new avenue of strategies for tissue repair."

She now 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 said.

She has initiated a collaboration with Jason Spector, MD, assistant professor of plastic surgery at Weill, and Larry Bonassar, PhD, 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 or after birth without the need of many surgeries.

Additional study collaborators were Rediet Zewdu and Victoria Wells, of Weill Cornell Medical College; Jean Hebert, of Albert Einstein College of Medicine; Courtney Karner, of the University of Texas, Southwestern Medical Center; Matthew Anderson, of the National Cancer Institute; Trevor Williams, of the University of Colorado; Jill Dixon and Michael Dixon, of the University of Manchester; and Michael Depew, of King's College London.

The research was supported by a Marie Curie Fellowship, the Medical Research Council in the United Kingdom, 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.




     

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