Epithelial hedgehog signals pattern the intestinal crypt-villus axis.
Morphological development of the small intestinal mucosa involves the stepwise remodeling of a smooth-surfaced endodermal tube to form finger-like luminal projections (villi) and flask-shaped invaginations (crypts). These remodeling processes are orchestrated by instructive signals that pass bidirectionally between the epithelium and underlying mesenchyme. Sonic (Shh) and Indian (Ihh) hedgehog are expressed in the epithelium throughout these morphogenic events, and mice lacking either factor exhibit intestinal abnormalities. To examine the combined role of Shh and Ihh in intestinal morphogenesis, we generated transgenic mice expressing the pan-hedgehog inhibitor, Hhip (hedgehog interacting protein) in the epithelium. We demonstrate that hedgehog (Hh) signaling in the neonatal intestine is paracrine, from epithelium to Ptch1-expressing subepithelial myofibroblasts (ISEMFs) and smooth muscle cells (SMCs). Strong inhibition of this signal compromises epithelial remodeling and villus formation. Surprisingly, modest attenuation of Hh also perturbs villus patterning. Desmin-positive smooth muscle progenitors are expanded, and ISEMFs are mislocalized. This mesenchymal change secondarily affects the epithelium: Tcf4/beta-catenin target gene activity is enhanced, proliferation is increased, and ectopic precrypt structures form on villus tips. Thus, through a combined Hh signal to underlying ISEMFs, the epithelium patterns the crypt-villus axis, ensuring the proper size and location of the emerging precrypt compartment.
Madison
Blair B
BB
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, USA.
Braunstein
Katherine
K
Kuizon
Erlene
E
Portman
Kathleen
K
Qiao
Xiaotan T
XT
Gumucio
Deborah L
DL
D000818:Animals; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000502:physiology; D008856:Microscopy, Fluorescence; D009130:Muscle, Smooth / Q000166:cytology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D019076:Transgenes; D051153:Wnt Proteins; D051176:beta Catenin
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; C026615:villin