Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters P J, Clevers H
Department of Immunology, University Hospital, Utrecht, The Netherlands.
Nat Genet. 1998 Aug;19(4):379-83. doi: 10.1038/1270.
Mutations of the genes encoding APC or beta-catenin in colon carcinoma induce the constitutive formation of nuclear beta-catenin/Tcf-4 complexes, resulting in activated transcription of Tcf target genes. To study the physiological role of Tcf-4 (which is encoded by the Tcf7/2 gene), we disrupted Tcf7/2 by homologous recombination. Tcf7/2-/- 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.
结肠癌中编码APC或β-连环蛋白的基因突变会诱导核β-连环蛋白/Tcf-4复合物的组成型形成，导致Tcf靶基因的转录激活。为了研究Tcf-4（由Tcf7/2基因编码）的生理作用，我们通过同源重组破坏了Tcf7/2。Tcf7/2-/-小鼠在出生后不久死亡。观察到单一的组织病理学异常。在大约胚胎第14.5天，肠内胚层向上皮的转变明显正常。然而，绒毛之间的预期隐窝区域没有维持增殖区室。因此，新生上皮完全由分化的、不分裂的绒毛细胞组成。我们得出结论，由Tcf-4控制的遗传程序维持小肠的隐窝干细胞。APC缺陷的人类上皮细胞中Tcf-4的组成型活性可能通过维持干细胞特征促进其恶性转化。
