Molecular mechanisms of intestinal epithelial gene transcription

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The intestinal epithelium is a highly dynamic renewal system organized in crypts, that are populated by proliferative cells, and villi composed of differentiated cells. Stem cells at the bottom of the crypts constantly produce precursor cells that undergo a succession of molecular changes that utimately lead to an arrest of proliferation and a commitment to differentiate. Although some clues have been collected over the past years on the nature of the molecular mechanisms that are required for the induction of cellular differentiation in this particular context, the regulatory circuit involved into the maintenance of intestinal epithelial cell proliferation that is required for continuous renewal of this epithelium still remains poorly defined. The progress of our research has led to the identification of a specific gene regulator (nuclear co-receptor repressor) as being crucial to maintain intestinal epithelial cell proliferation in culture. The pigment-epithelial-derived-factor gene, a potent inhibitor of cellular proliferation in a number of different cell systems, was identified to be down-modulated by the nuclear co-receptor repressor. The main objective of this proposal is further characterize the exact molecular mechanims by which the nuclear co-receptor repressor can target this gene and maintain intestinal epithelial cell proliferation. In addition, genetically modified mouse models will be generated in which the expression of the nuclear co-receptor repressor will be specifically impaired within the intestinal epithelium. These approaches should highlight the exact role for this regulator into normal intestinal epithelial physiology and in long term, contribute to the development of novel therapeutic tools for deregulated fonctions of the intestinal epithelium.