It is well recognised that the intestinal epithelium has a remarkable capacity to regenerate after high levels of DNA damage or injury. Although the kinetics of this clonogenic repopulation whereby a new stem cell repopulates the crypt is understood, little is known about the molecular mechanism underlying this, although upregulation of Musashi-1 is known to mark the process. By conditionally deleting genes that are lethal to the intestinal stem cells we have mimicked this process, with non-recombined stem cells repopulating the crypt, a scenario we define as genetic repopulation. During this repopulation process intestinal crypts become enlarged with an induction of proliferation, villi shorten and paneth cells become mislocalised. All of these traits are remarkably similar to the immediate phenotype following Apc loss within crypts. Consistent with this we find that Musashi-1 is upregulated in Apc deficient crypts in a c-Myc dependent manner. These observations suggested that activation of Wnt signalling drives the repopulation event, and indeed we observe nuclear relocalisation of nuclear beta-catenin and upregulation of two key wnt target genes, CD44 and C-MYC, in repopulating crypts. Taken together these data argue that activation of beta-catenin is not simply a tumorigenic event within the intestine but is essential for normal intestinal stem cell homeostasis.
01 - 05 Apr 2006
European Society of Endocrinology