New insight into one form of the birth defect synpolydactyly, where individuals have 1 or more digit (finger or toe) duplicated and 2 or more digits fused together, has now been provided by Stefan Mundlos and colleagues, at Universit?¤tsmedizin Berlin, Germany, who studied a mouse model of the condition.

One form of synpolydactyly is caused by mutations in the HOXD13 gene. To understand how these mutations cause disease the authors analyzed mice carrying one of these mutations, Spdh/Spdh mice. Surprisingly, the protein generated by the mutated gene was found to have lost a function of the normal Hoxd13 protein and to have gained a new function. Specifically, the mutant protein was unable to facilitate normal levels of production of the soluble factor RA, and intrauterine treatment with RA restored normal digit formation in Spdh/Spdh mice. As RA was shown to normally suppress the generation of cells that produce and maintain cartilage, the loss-of-function mutated Hoxd13 therefore indirectly promotes the formation of cartilage. Importantly, further analysis indicated the mutated protein also directly induced the generation of cells that produce and maintain cartilage, whereas normal Hoxd13 did not. Thus, mutated Hoxd13 causes syndpolydactyly by inducing the generation of cells that produce and maintain cartilage, both directly and indirectly.

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The investigators then tested their pieces of esophageal lining in whole animals. When the tissue-engineered patches were transplanted under the skin of immunodeficient mice, the cells formed epithelial structures. Additionally, in a mouse model of injury of the esophagus in a normal mouse, which mimics what happens during acid reflux, green-stained stem cells migrated to the injured lining cells and co-labeled with the repaired cells, indicating involvement of the stem cells in tissue repair and regeneration.

Eventually the researchers will develop genetically engineered mouse models to be able to track molecular markers of esophageal stem cells found in a micorarray study. The group has already developed a library of human esophageal cell lines and is looking for human versions of markers already identified in mice.

"The ultimate goal is to identify esophageal stem cells in a patient, grow the patient's own stem cells, and inject them locally to replace diseased tissue with normal lining," says Rustgi.

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