Basic—Alimentary TractDepletion of the Colonic Epithelial Precursor Cell Compartment Upon Conditional Activation of the Hedgehog Pathway
Section snippets
Mice
We used previously generated Ptch1flox/flox11 and Rosa26CreERT212 mouse lines. The Ptch1flox/flox mice had a loxP site inserted into intron 7 and intron 9 of the Ptch1 gene. The Rosa26CreERT2 mutant mouse strain expressed a fusion gene encoding Cre recombinase and a modified ligand-binding domain for the estrogen receptor under control of the endogenous Rosa26 promoter. The 2 mouse lines were crossed to obtain Ptch1flox/floxCreERT2+/− mice. Eight-week-old mice were injected intraperitoneally
Conditional Deletion of Ptch1 Exons 8 and 9 Activates Hh Targets in the Mesenchyme
Because conflicting data have been reported on the colonic expression of Ihh and Shh, possibly due to problems with antibody specificity, we reexamined their expression using a combination of immunohistochemistry and in situ hybridization. We found that Ihh messenger RNA (mRNA) was expressed by the differentiating epithelial cells in the midcrypt region (Figure 1A,left). In contrast to our previous in situ hybridizations of the human colon,7 we could not detect Shh mRNA in the mouse colon (
Discussion
Hhs are expressed throughout the adult gastrointestinal tract. Experiments that addressed the role of Hh signaling in the intestine up to now have either addressed its function during development and in the early postnatal period16, 32, 33 or relied on the use of cyclopamine, a pharmacologic Hh signaling inhibitor.2 Here we show that Ihh is the main Hh in the colon and signals from the epithelial cells to the mesenchyme. Conditional deletion of Ptch1 results in enhanced Hh signaling in the
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by a VENI grant from the Netherlands Organization for Scientific Research and by a grant from the Dutch Digestive Foundation.