The molecular mechanisms directing organ specific differentiation in the gastrointestinal tract are unknown. Complex interactions of multiple elements, including transcription factors, are necessary for the differentiation and development of the intestine and stomach. Cdx1 and Cdx2, intestine specific homeobox transcription factors, are candidate genes for directing intestinal development, differentiation and the maintenance of the intestinal phenotype. CDX1, though not in the normal stomach, is expressed in intestinal metaplasia of the gastric mucosa, suggesting a role in this pathologic process. The goal of this proposal is to determine, through two in vivo models the effect of Cdx1 and Cdx2 expression first, in early embryogenesis on undifferentiated endoderm and second, in differentiated intestine and stomach by conditional expression of the Cdx proteins. To examine Cdx expression in early embryogenesis, the coding region of Cdx1 and Cdx2 will be placed under the control of the Hnf3gamma promoter. In transgenic mice the Hnf3gamma/Cdx construct will direct premature expression of Cdx in the endoderm of the developing intestine and ectopic expression of Cdx in the developing stomach. The transgenic mice will be analyzed for morphologic changes in the intestine and stomach throughout embryogenesis. In addition, the stomach will be analyzed by in situ hybridization and immunohistochemistry to determine if Cdx1 or Cdx2 expression can alter the normal differentiation of the gastric mucosa, or induce the expression of intestine specific genes. A second set of transgenic animals will be constructed to study the effect of Cdx expression on differentiated gastric and intestinal mucosa. Expression of Cdx1 and Cdx2 will be under the control of a tetracycline inducible promoter for conditional expression of Cdx. These animals will be analyzed to determine the effect of Cdx expression on the proliferation and morphology of the intestinal epithelium and on the morphology and expression of intestinal specific genes in the stomach. The later will serve as a model for Cdx expression found in intestinal metaplasia of the gastric mucosa. These experiments are designed to elucidate the function of the intestine specific transcription factors Cdx1 and Cdx2 on the differentiation of the intestine and stomach in early embryogenesis or in weaned animals in order to further our understanding of some of the basic mechanisms involved in intestinal and gastric differentiation and the maintenance of organ specificity.
| Silberg, Debra G; Sullivan, Jessica; Kang, Eugene et al. (2002) Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122:689-96 |
