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Sonic hedgehog is essential to foregut development

Abstract

Congenital malformation of the foregut is common in humans, with an estimated incidence of 1 in 3000 live births1, although its aetiology remains largely unknown. Mice with a targeted deletion of Sonic hedgehog ( Shh) have foregut defects that are apparent as early as embryonic day 9.5, when the tracheal diverticulum begins to outgrow. Homozygous Shh-null mutant mice show oesophageal atresia/stenosis, tracheo-oesophageal fistula and tracheal and lung anomalies, features similar to those observed in humans with foregut defects. The lung mesenchyme shows enhanced cell death, decreased cell proliferation and downregulation of Shh target genes. These results indicate that Shh is required for the growth and differentiation of the oesophagus, trachea and lung, and suggest that mutations in SHH and its signalling components may be involved in foregut defects in humans.

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Figure 1: Foregut defects and lung hypoplasia in Shh-/- mutant.
Figure 2: Oesophageal atresia/stenosis and tracheo-oesophageal fistula in 17.5 dpc Shh-/- mutant.
Figure 3: Shh is essential in lung development.
Figure 4: Epithelial and mesenchymal gene expression in Shh-/- mutant lungs.

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Acknowledgements

We would like to thank B. Hogan for helpful comments and suggestions on the manuscript. We also thank C.-c. Hui for communicating the unpublished data. We acknowledge the help of P. Anastasiadis in analysing the BrdU data and J. Kong for the apoptosis experiment. We thank C.-c. Hui, H. Sasaki, B. Hogan, C. Deng, S.-J. Lee, M. Scott and S. Kimura for providing the cDNA probes. Our thanks also go to Y. Furuta and S. Bellusci for providing suggestions and reagents. We are grateful to V. Winfrey and L. Hoffman for letting us use their cryostat.

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Correspondence to Chin Chiang.

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Litingtung, Y., Lei, L., Westphal, H. et al. Sonic hedgehog is essential to foregut development. Nat Genet 20, 58–61 (1998). https://doi.org/10.1038/1717

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