Wnt signalling in the mouse intestine

The Apc(Min/+) mouse has emerged as a powerful model of human intestinal tumour predisposition. As such, it has provided a platform for studying genetic and epigenetic modifiers of adenoma predisposition, and for assessing the chemotherapeutic potential of a plethora of different agents. The development of new conditional and hypomorphic Apc alleles, together with models carrying mutations in other Wnt pathway components, has greatly extended the scope of experimentation. Together these approaches are being used to identify and validate key critical targets of the Wnt pathway, such as Mash2, Tiam1 and the Eph/Ephrins. They have also established a fundamental role for Wnt in the development and maintenance of normal intestinal physiology, and in particular control of the stem cell niche. These activities are now being dissected at the level of individual Wnt components, with some surprising dependencies revealed. In terms of adenoma development, these models also support a 'just right' notion for tightly controlled beta-catenin activity both in normal physiology and neoplastic development. They also indicate a two-stage dependency for some Wnt pathway targets, with an initial requirement that is subsequently overcome to permit progression. Finally, these models establish that the Wnt pathway does not operate in isolation, and that both normal and diseased physiology develops in a dynamic interplay with other pathways such as the Notch, Hedgehog and BMP pathways. The comprehensive understanding arising from these studies should lead the identification of novel prognostic markers and therapeutic targets, and also open the possibility of tissue engineering in the intestine.