Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice

To determine the biological role of caudal-like homeobox gene CDX2, we cons tructed knockout mice in which its mouse homologue Cdx2 was inactivated, by homologous recombination, placing a bacterial lacZ gene under the control of the Cdx2 promoter. Although the homozygous mutants died in utero around implantation, the heterozygotes were viable and fertile and expressed lacZ in the caudal region in early embryos and in the gut tissues in adults. The heterozygotes developed cecal and colonic, villi by anteriorization and fo rmed hamartomatous polyps in the proximal colon. The hamartoma started to d evelop at 11.5 days of gestation as an outpocket of the gut epithelium, whi ch ceased to express the remaining Cdx2 allele. The outpocket then expanded as a partially duplicated gut but was contained as a hamartoma after birth . In adult mice, these hamartomas grew very slowly and took a benign course . None of them progressed into invasive adenocarcinomas, even at 1.5 years of age, Whereas the cecal and colonic, villi expressed lacZ, the hamartoma epithelium did not, nor did it express Cdx2 mRNA from the wild-type allele, However, genomic DNA analysis of the polyp epithelium did not show a loss of heterozygosity of the Cdx2 gene, suggesting a mechanism of biallelic Cdx 2 inactivation other than loss of heterozygosity. These results indicate th at the Cdx2 haploin-sufficiency caused cecal and colonic villi, whereas the biallelic inactivation of Cdx2 triggered anomalous duplications of the emb ryonic gut epithelium, which were contained as hamartomas after birth.