Abstract
In mammals, the Wnt/β-catenin signal transduction pathway regulates intestinal stem cell maintenance and proliferation, whereas Wnt pathway hyperactivation, resulting primarily from the inactivation of the tumor suppressor Adenomatous polyposis coli (APC), triggers the development of the vast majority of colorectal cancers. The Drosophila adult gut has recently emerged as a powerful model to elucidate the mechanisms by which Wingless/Wnt signaling regulates intestinal development, homeostasis, regeneration, and tumorigenesis. Herein, we review recent insights on the roles of Wnt signaling in Drosophila intestinal physiology and pathology.
Highlights
In mammals, the Wnt/β-catenin signal transduction pathway regulates intestinal stem cell maintenance and proliferation, whereas Wnt pathway hyperactivation, resulting primarily from the inactivation of the tumor suppressor Adenomatous polyposis coli (APC), triggers the development of the vast majority of colorectal cancers
Controversy remains regarding the requirement for Wg signaling in intestinal stem cells (ISCs) self-renewal, as: (1) ISC self-renewal is not affected upon concomitant inactivation of Apc1 and Apc2 in the posterior midgut [142]; (2) concomitant knockdown of wg from epithelial and muscle sources or in wgCX4 heterozygous mutants does not lead to significant loss of posterior midgut ISCs even after 30 days [113]; and, (3) in contrast with the effects of dominant negative TCF overexpression, inactivation of core Wnt pathway components with null alleles results only in mild effects on ISC maintenance during homeostasis [104]
With the knowledge gained from these models, the order of drug treatment was manipulated to promote drug sensitivity in Drosophila tumor cells, and this approach was subsequently validated in mammalian models [103]. These findings demonstrate that the Drosophila adult digestive tract recapitulates key events in both the initiation and progression of tumorigenesis following APC loss, and offers a promising platform for both drug screening and the identification of novel tumor modifiers
Summary
Akin to the functional segmentation of the mammalian gastrointestinal tract [75,76,77,78,79,80], the Drosophila gut is subdivided into foregut, midgut, and hindgut, based on their distinct developmental origin and function. Similar to that in its mammalian counterpart, Drosophila gut compartmentalization facilitates the sequential digestion of food and absorption of nutrients, as well as defense against infection. Resembling the mammalian digestive tract, the Drosophila adult midgut is comprised of a monolayer epithelium that is replenished regularly by ISCs [85,87,88]. The ability to mark and manipulate stem cell lineages, to abrogate or to overactivate Wg signaling at defined time points, to study epithelial regeneration following injury, and to examine intestinal epithelial cell division, differentiation, and niche-stem cell contacts at the single cell level all add to the advantages of using Drosophila to study Wnt-driven physiology and pathology [91,95,96,97,98,99]. The Drosophila gut provides a powerful physiological context to test both novel Wnt pathway components and novel therapeutic agents that target the pathway [100,101,102,103]
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