Basic ResearchCdx2 ectopic expression induces gastric intestinal metaplasia in transgenic miceā,āā
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Generation of the Foxa3/Cdx2 yeast artificial chromosome
The Cdx2-expressing transgenic construct was made using a yeast artificial chromosome (YAC) clone containing the complete Foxa3 locus (previously Hnf3Ī³). A āpop-in, pop-outā approach was used to introduce the Cdx 2 complementary DNA (cDNA) into a 170-kilobase (kb) Foxa3-YAC (Figure 1).29
The derivation of Cdx2-expressing transgenic animals
Cdx2 expression in the gastric mucosa was achieved through the derivation of transgenic mice in which the mouse Cdx2 cDNA was under the control of the cis-regulatory elements of the winged helix transcription factor Foxa3 in a YAC.29 The Foxa3-YAC had been shown previously to direct copy-numberādependent and integration siteāindependent expression of a transgene to the glandular gastric mucosa.29 The Cdx2 cDNA was incorporated into the Foxa3 YAC via homologous recombination in yeast as outlined
Discussion
We report that ectopic expression of Cdx2, a homeodomain transcription factor, in the gastric mucosa causes transdifferentiation of the epithelium to an intestinal type, providing the first causal link between Cdx2 expression and intestinal metaplasia. The histologic and molecular changes induced by the expression of Cdx2 in the stomach mimic the changes observed in human intestinal metaplasia, namely the appearance of goblet cells and the activation of intestinal genes in the gastric
Acknowledgements
The authors thank P. G. Traber for his guidance and mentoring, A. K. Rustgi and G. D. Wu for advice and discussions, and S. Mancano for technical assistance.
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Address requests for reprints to: Debra G. Silberg, M.D., Ph.D., University of Pennsylvania, 415 Curie Boulevard, 650 CRB, Philadelphia, Pennsylvania 19104. e-mail: [email protected]; fax: (215) 573-2024.
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This work was supported by NIH-NIDDK grants K08-DK02375, R03-DK56082, and R01-DK69539 (to D.G.S.), R01-DK53839 (to K.H.K.), and the Morphology, Molecular Biology and Transgenic Cores of the Center for Molecular Studies in Digestive Disease at the University of Pennsylvania (P30-DK50306).