The gastrointestinal epithelium undergoes rapid and perpetual renewal. Multipotent stem cells give raise to daughter cells that produce a variety of terminally differentiated cell types. This process of proliferation/differentiation is remarkably well organized in a number of spatial dimensions. The molecular mechanisms that underlie the establishment and maintainence of this geographic differentiation are poorly understood. This grant proposal focuses on the use of transgenic mice to map cis-acting elements that regulate cell-specific and region- specific patterns of expression of genes in the gastric epithelium. The oxyntic glands of the stomach contain four distinct types of exocrine cells as well as a number of endocrine cells. Neither their lineage relationships nor their differentiation pathways are well understood. Intrinsic factor (IF) gene transcription is restricted to the chief and parietal cells of oxyntic glands. We will link various portions of the mouse IF gene's 5' nontranscribed domain to a reporter- the human growth hormone gene - and define the resulting patterns of HGH expression in the gastrointestinal tract of transgenic mice. RNA blot hybridization and immunocytochemical methods will be used for these analyses. This will allow us to functionally map cis-acting elements in the mouse IF gene that regulate is foregut-specific and cell-specific expression. These studies should provide insights about the mechanisms that modulate gene expression in differentiating gastric epithelial cell populations.
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