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. 2012 Jan 27;62(1):83–93. doi: 10.1136/gutjnl-2011-301601

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Individual crypt Wnt target gene expression varies longitudinally throughout the normal mouse and human intestinal tract. Thumbnail pictures show whole mount intestinal crypts and villi from the different regions of normal mouse and human intestine after EDTA extraction. Mouse villi are pictured purely to provide scale; in fact, only individual crypts were aspirated and used in analysis. Mesenchymal tissue was isolated after complete epithelial denudement. Scale bar 100 μm. Five crypts were dissected from each intestinal region, analysed individually and used to calculate a mean ΔCt, which was then averaged across three wild-type mice (online supplementary table 2A) and four human patients (online supplementary table 2B). Mean ΔΔCt values were used to calculate expression fold changes compared with the region of minimal expression. (A) Mouse gene expression category 1 Wnt target genes (transit amplifying cells) showed quite variable expression along the intestine but were maximally expressed in the proximal small bowel (SB1) (with the exception of Cyclin D1). Category 2 genes (Paneth cells) were expressed in the small intestine as expected from this cell distribution (p<0.001, analysis of variance (ANOVA)). Category 3 genes (stem-cell zone) showed very similar expression profiles with maximal expression in the small intestine declining markedly in the colon with minimal expression seen in the caecum (p<0.001, ANOVA). Sox4 expression closely mirrored that of Ascl2 and a striped line indicates the regions of identical expression. Conversely, epithelial Bmp2 expression was minimal in the duodenum climbing steadily to a peak in the mouse rectum (p<0.001, ANOVA), and there was also significant variability in the expression of some of the mesenchymal Wnt modulators (Grem2 and Hgf, p<0.05, ANOVA). The expression of the mesenchymal Wnt antagonist, Sfrp2, varied considerably with colonic expression more than 130-fold greater than that in the small intestine (p=0.035, ANOVA). (B) Human gene expression. All human Wnt target genes were maximally expressed in the ileum and minimally expressed in the rectum with the exception of the category 1 genes LEF1 and CYCLIN D1 (CCND1), which were maximally expressed more proximally. Category 3 (stem-cell) gene expression peaked in the ileum correlating with the human in situ findings (p<0.001, ANOVA). Caecal stem-cell marker expression is significantly greater than that seen in the rectum. The inverse correlation was seen for epithelial BMP2 expression (p<0.001, ANOVA). Expression of the mesenchymal Wnt modulators was generally higher in the human small intestine which contrasted sharply with the murine Gremlin 1, 2 and Sfrp2 expression gradients. Only the expression gradient for HGF reached statistical significance in the humans (p=0.05, ANOVA) as the result of a 10-fold difference in expression from the caecum to the rectum. SB1, proximal small bowel; SB2, mid-small bowel; SB3, distal small bowel.