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 cancers, causes constitutive, ligand-independent signaling through the Hedgehog pathway, and provides a powerful means to test effects of unregulated Hedgehog signaling. Expression of SmoM2 in Xenopus embryos leads to developmental anomalies that are consistent with known requirements for regulated Hedgehog 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 exception of the pancreas, differentiation of foregut and hindgut derivatives is unaffected. The intestinal epithelial abnormalities are reproduced in embryos or organ explants treated directly with active recombinant hedgehog protein. Ptc mRNA, a principal target of Hedgehog signaling, is maximally expressed 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 the transition of midgut endoderm into intestinal epithelium and that attenuation of this feedback is required for normal development of the vertebrate intestine.
Zhang
J
J
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Rosenthal
A
A
de Sauvage
F J
FJ
Shivdasani
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D004627:Embryonic Induction; D004707:Endoderm / Q000502:physiology; D015723:Gene Library; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000196:embryology*; D007421:Intestine, Small / Q000196:embryology*; D008648:Mesoderm; D008954:Models, Biological; D008969:Molecular Sequence Data; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D014982:Xenopus laevis
D053823:Hedgehog Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators