Targeted Disruption Of Smad4 In Mouse Gut Epithelium Results In Gastrointestinal Adenoma

Smad4 is the common mediator of the transforming growth factor-β(TGF-β) superfamily that functions in diverse developmental processes in mammals, such as regulating cell proliferation, differentiation, migration, adhension and apoptosis. Since the complete knockout of Smad4 results in embroyic lethality, we generated a gut epithelium specific Smad4 gene knockout mouse strain using Cre-loxP system to investigate the function of Smad4 in gastrointestinal epithelium.We used PCR and LacZ staining to identify the tissue distribution and the Cre recombinase activity in the Cre transgenic mouse line (Alb-Cre-2) which expresses the Cre recombinase under the control of a mouse albumin gene promoter. PCR results revealed that the Smad4 gene was deleted by Cre mediated recombination in the gastro-intestinal tissues, liver, lung, panCreas and brain. LacZ staining of the albumin-Cre and ROSA26 double transgenic mice showed that Cre recombinase activity was detected in hepatocytes, gastric parietal cells, jejunum paneth cells, ileum goblet cells and also colon mucosa cells.The albumin-Cre-2 transgenic mice were bred with mouse strains carrying the conditional targeted Smad4 alleles to obtain the liver and gut epithelium specific Smad4 gene knockout mice. The Smad4 mutant mice died of gastrointestinal polyps between 1.5 and 6.5 months after birth. The tumor incidence in stomach, small intestine, cecum, colon and rectum is 91.30%,13.04%,34.78%,56.52% and 21.74% respectively. Histological ananlysis indicated that all the gastrointestinal tumors developed in Smad4 mutants are adenomas. The nature history and pathological features of the gastrointestinal adenoma in Smad4 mutant mice were very similar with...