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Cleft lip corrected genetically in mouse model
Date:11/28/2011

ing 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.
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Contact: Takla Boujaoude
tab2016@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Source:Eurekalert

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