Downregulation of hedgehog signaling is required for organogenesis of the small intestine in Xenopus

Hedgehog ligands interact with receptor complexes containing Patched (PTC) and Smoothened (SMO) proteins to regulate many aspects of development. The mutation W535L (SmoM2) in human Smo is associated with basal cell skin canc ers, causes constitutive, ligand-independent signaling through the Hedgehog pathway, and provides a powerful means to test effects of unregulated Hedg ehog signaling. Expression of SmoM2 in Xenopus embryos leads to development al anomalies that are consistent with known requirements for regulated Hedg ehog signaling in the eye and pancreas. Additionally, it results in failure of midgut epithelial cytodifferentiation and of the intestine to lengthen and coil. The midgut mesenchyme shows increased cell numbers and attenuated expression of the differentiation marker smooth muscle actin. With the exc eption of the pancreas, differentiation of foregut and hindgut derivatives is unaffected. The intestinal epithelial abnormalities are reproduced in em bryos or organ explants treated directly with active recombinant hedgehog p rotein. Ptc mRNA, a principal target of Hedgehog signaling, is maximally ex pressed at stages corresponding to the onset of the intestinal defects. In advanced embryos expressing SmoM2, Ptc expression is remarkably confined to the intestinal wall. Considered together, these findings suggest that the splanchnic mesoderm responds to endodermal Hedgehog signals by inhibiting t he transition of midgut endoderm into intestinal epithelium and that attenu ation of this feedback is required for normal development of the vertebrate intestine. (C) 2001 Academic Press.