Abstract
Congenital malformation of the foregut is common in humans, with an estimated incidence of 1 in 3000 live births, 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.
MeSH terms
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Animals
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endoderm / metabolism
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Esophagus / abnormalities
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Esophagus / embryology*
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Esophagus / metabolism
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Gene Expression Regulation, Developmental
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Hedgehog Proteins
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Immunohistochemistry
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In Situ Hybridization
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Kruppel-Like Transcription Factors
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Lung / abnormalities
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Lung / embryology*
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Lung / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mesoderm / metabolism
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Mice
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Mice, Knockout
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Nerve Tissue Proteins*
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Organ Culture Techniques
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Patched Receptors
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Proteins / genetics*
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Proteins / metabolism
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Receptors, Cell Surface
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Repressor Proteins*
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Time Factors
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Trachea / abnormalities
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Trachea / embryology*
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Trachea / metabolism
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Trans-Activators*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Xenopus Proteins*
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Zinc Finger Protein Gli3
Substances
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DNA-Binding Proteins
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GLI3 protein, Xenopus
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GLI3 protein, human
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Gli3 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Membrane Proteins
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Nerve Tissue Proteins
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Patched Receptors
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Proteins
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Receptors, Cell Surface
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Repressor Proteins
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SHH protein, human
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Trans-Activators
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Transcription Factors
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Xenopus Proteins
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Zinc Finger Protein Gli3