Abstract
Foregut malformations (oesophageal atresia, tracheo-oesophageal fistula, lung anomalies and congenital stenosis of the oesophagus and trachea) are relatively common anomalies occurring in 1 in 2,000-5,000 live births, although their aetiology is poorly understood1. The secreted glycoprotein Sonic hedgehog (Shh) has been suggested to act as an endodermal signal that controls hindgut patterning2 and lung growth3. In mice, three zinc-finger transcription factors, Gli1, Gli2 and Gli3, have been implicated in the transduction of Shh signal4,5,6,7,8,9,10. We report here that mutant mice lacking Gli2 function exhibit foregut defects, including stenosis of the oesophagus and trachea, as well as hypoplasia and lobulation defects of the lung. A reduction of 50% in the gene dosage of Gli3 in a Gli2–/– background resulted in oesophageal atresia with tracheo-oesophageal fistula and a severe lung phenotype. Mutant mice lacking both Gli2 and Gli3 function did not form oesophagus, trachea and lung. These results indicate that Gli2 and Gli3 possess specific and overlapping functions in Shh signalling during foregut development, and suggest that mutations in GLI genes may be involved in human foregut malformations.
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Acknowledgements
We thank C. Chiang and B. Hogan for sharing unpublished data, M. Crackower and H. Lipshitz for suggestions on the manuscript and B. Hogan, G. Martin, A. McMahon, H. Sasaki, J. Rossant and M. Scott for reagents. This work was supported by the National Cancer Institute of Canada (C.-c.H.), Ontario Thoracic Society (C.-c.H. & M.P.) and Medical Research Council of Canada (M.P.).
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Motoyama, J., Liu, J., Mo, R. et al. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 20, 54–57 (1998). https://doi.org/10.1038/1711
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DOI: https://doi.org/10.1038/1711
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