Hedgehog signals regulate multiple aspects of gastrointestinal development

The gastrointestinal tract develops from the embryonic gut, which is compos ed of an endodermally derived epithelium surrounded by cells of mesodermal origin, Cell signaling between these two tissue layers appears to play a cr itical role in coordinating patterning and organogenesis of the gut and its derivatives. We have assessed the function of Sonic hedgehog and Indian he dgehog genes, which encode members of the Hedgehog family of cell signals. Both are expressed in gut endoderm, whereas target genes are expressed in d iscrete layers in the mesenchyme. It was unclear whether functional redunda ncy between the two genes would preclude a genetic analysis of the roles of Hedgehog signaling in the mouse gut. We show here that the mouse gut has b oth common and separate requirements for Sonic hedgehog and Indian hedgehog . Both Sonic hedgehog and Indian hedgehog mutant mice show reduced smooth m uscle, gut malrotation and annular pancreas, Sonic hedgehog mutants display intestinal transformation of the stomach, duodenal stenosis (obstruction), abnormal innervation of the gut and imperforate anus. Indian hedgehog muta nts show reduced epithelial stem cell proliferation and differentiation, to gether with features typical of Hirschsprung's disease (aganglionic colon). These results Show that Hedgehog signals are essential for organogenesis o f the mammalian gastrointestinal tract and suggest that mutations in member s of this signaling pathway may be involved in human gastrointestinal malfo rmations.