Basic—Alimentary TractIndian Hedgehog Regulates Intestinal Stem Cell Fate Through Epithelial−Mesenchymal Interactions During Development
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Mice
The Ihhflox/flox mice were provided by Dr Beate Lanske of Harvard University.14Villin-Cre mice15 and Smoflox/flox mice16 were obtained from the Jackson Laboratory. Ihhflox/flox and Villin-Cre mice were mated and the offspring were backcrossed to generate Villin-Cre;Ihhflox/flox mice. Genotyping was performed by polymerase chain reaction on genomic DNA from tail clips as described previously.14, 15 The Villin-Cre; Ihhflox/flox pups suffer early lethality and were sacrificed when they displayed
Generation of Ihh-Conditional Knockout Mice
A partial description of Ihh's role in intestinal development has been provided by 2 studies of Ihh−/− mice: 1 study described a loss of proliferative epithelial cells in Ihh−/− mice,10 while the second study noted an expansion of proliferative epithelial cells in Ihh−/− mice.18 However, Ihh−/− mice die at birth, precluding any analysis of Ihh's role during postnatal intestinal development. To examine the full role of Ihh in intestinal development, including the critical postnatal period when
Discussion
The epithelial phenotypes we observed in the Villin-Cre;Ihhflox/flox mice are, overall, consistent with other mouse models that disrupt Hh signaling during gut morphogenesis, such as mice overexpressing the Hh inhibitor Hhip, or mice with a conditional deletion of Ptch1.12, 13 However, none of the previous studies addressed the critical question of whether paracrine Hh signaling affects ISC self-renewal or whether the epithelial phenotypes are due to the disruption of
Acknowledgments
We thank Dr Beate Lanske of Harvard University for providing us with the Ihhflox/flox mice and Sandra Huling of the UCSF Liver Center for histology and electron microscopy support.
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Transcript profiling: The raw data of microarray experiment are available at Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/projects/geo) under the accession number of GSE18393.
Conflicts of interest The authors disclose no conflicts.
Funding This work is supported in part by National Institutes of Health grants R21DK069309 and R01CA136606 to X.C.; R01CA127229 and R01DK55783 to D.W.P.; a grant from the Research Grants Council of the Hong Kong Special Administrative Region (Project No. HKU7524/06M) to S.Y.L. and X.C.; a grant from Strategic Research Theme on Cancer from The University of Hong Kong to S.Y.L. C.K. is supported by a stem cell fellowship provided by the California Institute for Regenerative Medicine; and D.E.S. is supported by Deutsche Forschungsgemeinschaft (DFG, Sta1065/1-1). The funding agencies have no role in data collection, analysis, and interpretation.