The intestine absorbs nutrients from ingested food, a function that is facilitated by fingerlike projections of the epithelium called villi, which increase the surface area of the intestine. Formation of villi is attenuated in mice with decreased signaling through the Hedgehog (Hh) pathway. Using mice with LacZ reporter genes to indicate expression patterns of Patched1 (Ptc1) or Gli1, which encode a receptor and transcription factor involved in Hh signal transduction, Walton et al. found that clusters of Ptc1- or Gli1-positive mesenchymal cells appeared before formation of villi, which subsequently emerged directly above the clusters. Platelet-derived growth factor receptor α (PDGFRrα) is required for formation of villi, and in mice with a reporter gene to indicate the expression pattern of Pdgfrα (in which a fluorescently tagged protein was driven by the Pdgfrα promoter) as well as the LacZ reporter gene for Patched1 or Gli1, the majority of cells in clusters of Ptc1- or Gli1-positive mesenchymal cells were also positive for Pdgfrα. Villi emerge in the intestine in an anterior-to-posterior wave, and the mesenchymal clusters of Pdgfrα-positive cells formed in a similarly oriented wave, but before the emergence of villi. Statistical analysis of the distribution of the mesenchymal clusters indicated that they emerged in a nonrandom, patterned array. In an explant system using intestines from embryonic mice expressing the reporter gene for Pdgfrα, inhibition of Hh signaling with the antagonist cyclopamine attenuated the formation of mesenchymal cell clusters and villi, whereas stimulating Hh signaling with the agonist SAG increased the size and width of the clusters and villi. Thus, Hh signaling in clusters of mesenchymal cells dictates villus formation from the intestinal epithelium.
K. D. Walton, Å. Kolterud, M. J. Czerwinski, M. J. Bell, A. Prakash, J. Kushwaha, A. S. Grosse, S. Schnell, D. L. Gumucio, Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi. Proc. Natl. Acad. Sci. U.S.A. 109, 15817–15822 (2012). [Abstract] [Full Text]