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Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4

Abstract

Mutations of the genes encoding APC or ß-catenin in colon carcinoma induce the constitutive formation of nuclear ß-catenin/Tcf-4 complexes, resulting in activated transcription of Tcf target genes1,2. To study the physiological role of Tcf-4 (which is encoded by the Tcf7l2 gene), we disrupted Tcf7l2 by homologous recombination. Tcf7l2-/- mice die shortly after birth. A single histopathological abnormality was observed. An apparently normal transition of intestinal endoderm into epithelium occurred at approximately embryonic day (E) 14.5. However, no proliferative compartments were maintained in the prospective crypt regions between the villi. As a consequence, the neonatal epithelium was composed entirely of differentiated, non-dividing villus cells. We conclude that the genetic program controlled by Tcf-4 maintains the crypt stem cells of the small intestine. The constitutive activity of Tcf-4 in APC-deficient human epithelial cells may contribute to their malignant transformation by maintaining stem-cell characteristics.

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Figure 1: Targeted disruption of Tcf7l2.
Figure 2: Tcf-4 protein is absent in Tcf7l2-/- mice.
Figure 3: Embryonic development of the small intestine in Tcf7l2-/- mice.
Figure 4: Cytodifferentiation in the small intestine of Tcf7l2-/- mice.
Figure 5: Ultrastructural investigations show a defect in the intervillus region.
Figure 6: Absence of cycling cells in Tcf7l2-/- small intestinal epithelium.

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Acknowledgements

We thank F. Hofhuis, M. Girma and S. Verbeek for blastocyst injections and breeding of the chimaeric mice, D. Acton for the mouse genomic library, M. Schilham for help in the gene targeting experiment, V. Timmermans and S. Pals for the Grimelius stainings and H. Bos and T. Logtenberg for critically reading the manuscript. We also thank J. de Groot, M. Niekerk and R. Scriwanek for photography, W. Verrijp for digital prints and M. van de Wetering for help in preparing the manuscript.

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Correspondence to Hans Clevers.

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Korinek, V., Barker, N., Moerer, P. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19, 379–383 (1998). https://doi.org/10.1038/1270

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