Inducible Cre-Mediated Control of Gene Expression in the Murine Gastrointestinal Tract: Effect of Loss of β-Catenin

Abstract

Background & Aims: A system for introducing specific gene mutations into the epithelia of the adult murine gastrointestinal tract by the transcriptional regulation of Cre recombinase is presented and applied to delete β-catenin, a central mediator of Wnt signaling, within the small intestine (SI). Methods: In a transgenic line (Ahcre), cre expression is inducible from a cytochrome P450 promoter element that is transcriptionally up-regulated in response to lipophilic xenobiotics such as β-napthoflavone. Results: Recombination at a lacZ reporter locus showed extensive expression of β-galactosidase in liver, intestine, pancreas, gallbladder, esophagus, and stomach in response to β-napthoflavone treatment. Expression patterns were stable in renewing epithelia for at least 6 months, implying that long-lived stem cells undergo recombination. Analysis of the intestinal epithelium showed dose responsiveness in the extent of recombination and that villus and crypt populations could be targeted differentially by varying the route of administration of β-napthoflavone. The use of this system to delete β-catenin in the SI caused crypt ablation, increased apoptosis, depleted numbers of goblet cells, and detachment of villus absorptive cells from the villus core as intact sheets. Conclusions: The Ahcre model provides a simple route for introducing specific gene mutations into many of the epithelia of the gastrointestinal tract of the mouse. It has been used here to show that β-catenin is required for the maintenance of intestinal cell proliferation and is implicated in goblet cell differentiation and enterocyte-matrix attachment.