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 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.

Regulation of adult intestinal epithelial stem cell development by thyroid hormone during Xenopus laevis metamorphosis

“…Indeed, the Shh/BMP-4 signaling pathway shown to be involved in the amphibian intestinal remodeling has also been proposed to play roles in the embryonic gut organogenesis of terrestrial vertebrates (Roberts, 2000;Zhang et al, 2001; and the postembryonic epithelial cell-renewal of the mammalian intestine (Howe et al, 2001;Madison et al, 2004;Haramis et al, 2004;He et al, 2004He et al, , 2007Batts et al, 2006). Mutations in members of this pathway are known to be associated with the numerous malformations (Litingtung et al, 1998;Ramalho-Santos et al, 2000) and diseases (Howe et al, 2001;de Santa Barbara et al, 2002Berman et al, 2003;Beachy et al, 2004;He et al, 2004;Nielsen et al, 2004). However, their precise functions, while likely conserved throughout terrestrial vertebrates, are not yet fully understood.…”

Sonic hedgehog signaling pathway in vertebrate epithelial appendage morphogenesis: perspectives in development and evolution

“…Shh is expressed ventrally in the foregut endoderm, the precursor of the lung epithelium [48]. At E 11.5, Shh is expressed at low levels throughout the epithelium.…”

“…The role of SHH in foregut development was demonstrated in Shh knockout mice [48,52]. By E 12.5, the trachea and esophagus are normally separated, but in Shh null mutants, the trachea and esophagus do not separate appropriately.…”

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

“…This serves to control end bud size and shape by preventing widespread FGF-10 expression in the mesenchyme and FGFR-2B overactivation in the epithelium. Mice with targeted deletion of Shh or ectopic overexpression of Shh in the distal bud display severe defects in lung development, indicating an essential role for Shh in the branching process (Bellusci et al, 1997;Litingtung et al, 1998;Pepicelli et al, 1998).…”