The intestinal epithelium represents one of the richest and easy reachable sources of adult Stem Cells. Each of the million crypts that decorate the intestinal mucosa contains a handful of adult Stem Cells with unlimited capacity of self-renewal. Yet its u se has been hampered by the lack of knowledge regarding the programs and pathways controlling their maintenance and specification. Recent data indicate that Wnt signalling might play a general role in Stem Cell specification as that it is essential for Intestinal Stem Cell renewal. Here we propose to study further these questions into three steps or objectives. First, we intend to establish long term intestinal stem cell cultures and to study their potential in the regeneration of other tissues. Second, we propose to identify and characterize the core beta-catenin/Tcf genetic program (effector of Wnt signalling in the nucleus) driving specification or maintenance of diverse types of embryonic and adult Stem Cells including Intestinal Stem Cells. Third, we wi ll characterize the mechanisms of intestinal cell positioning at the bottom of the crypts and the role of cell repulsion mediated by Eph and ephrins - two beta-catenin/Tcf targets - in controlling cell sorting in the intestinal epithelium.
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