1999 Fiscal Year Final Research Report Summary
Research of the polyp formation in the intestine using Knock-out mouse
| Project/Area Number |
10307002
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TAKATO M. Makoto Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Professor, 大学院・薬学系研究科, 教授 (70281714)
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| Co-Investigator(Kenkyū-buntansha) |
SASAKI Nobuya Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Assistant Professor, 大学院・薬学系研究科, 助手 (20302614)
MATSUI Minoru Dept. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Position. Assistant Professor, 大学院・薬学系研究科, 助手 (50282611)
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| Project Period (FY) |
1998 – 1999
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| Keywords | APC / TGF-B / Smad 4 / beta-catenin / Cdx-2 / Cdx-2 |
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| Research Abstract |
(1) Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice.
We constructed knockout mice in whichSmad4 was inactivated by homologous recombination. Although simple Smad4 homozygotes were embryonically lethal, the heterozygotes were fertile and appeared normal up to the age of I year. Upon further investigation, however, they have developed inflammatory polyps in the glandular stomach and duodenum. Histologically, the polyps are similar to human juvenile polyps showing moderate stromal bell proliferation and infiltrations by eosinophils and plasma cells. In addition, foci of adenocarcinoma with, signet ring cells ate also found. These results are consistent with a recent report that germ-line SMAD4 mutations are found in a subset of familial juvenile polyposis.
(2) Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene.
Ectopic expression of certain Wnt genes in mouse mammary tissue is tumorigenic, and mutations that stabilize beta-catenin are found in var
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ious human canters including colorectal cancer. To determine the role of stabilized beta-catenin in intestinal tumorigenesis in mice, we constructed by embryonic stem (ES) cell-mediated homologous recombination, a mutant beta-catenin allele which caused adenomatous intestinal polyps resembling those in Apc knockout mice. These results present experimental genetic evidence that activation of the Wnt signaling pathway can cause intestinal and colonic tumors.
(3) Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice.
To determine the biological role of caudal-like homeobox gene Cdx2, we constructed Cdx2 knockout mice by homologous recombination. Although the homozygous mutants died in utero around implantation, the heterozygotes were viable and fertile. The heterozygotes developed cecal and colonic villi by anteriorization and formed hamartomatous polyps in the proximal colon. Several experiments indicate that the Cdx2 haploin-sufficiency caused cecal and colonic villi, whereas the biallelic inactivation of Cdx2 triggered anomalous duplications of the embryonic gut epithelium, which were contained as hamartomas after birth. Less
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