Conserved mechanisms in epithelial niche regulation of intestinal stem cells

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Project Summary The goal of this proposal is to dissect the underlying mechanism of the Tao and TAOK subfamily of Ste20 kinases in mediating mechanosensing and tissue growth in both Drosophila and mouse intestines. Billions of cells in the human gastrointestinal (GI) tract epithelium are shed and replaced every day. This fast pace of cell replacement also allows the intestine to afford adaptive growth, during which the epithelium can expand or shrink rapidly according to the need. Mechanistic study of tissue homeostasis in the human GI tract epithelium is, however, rather difficult because of the complexity of cell types, pathways and microbes involved. The Drosophila midgut has a similar but yet simpler anatomy and physiology than mammalian intestines. With highly cell-specific markers and sophisticated genetic techniques available, as well as a short life cycle to allow multiple generations of in vivo experiments, the Drosophila midgut has become a highly valuable system to study complex intestinal biology. We have recently discovered a novel function of the Drosophila Ste20 kinase Misshapen that mediates food particle ingestion caused mechanical stretching signal to regulate growth. Another Ste20 kinase Tao functions upstream, and may link the membrane mechanosensing components to Misshapen and downstream growth signaling. This pathway is well-conserved in mammals, with homologs of Misshapen (MINK1, MAP4K4, and TNIK), as well as other Ste20 kinases including Hippo (MST1 andMST2), can similarly interact with the downstream components LATS and YAP. The functional analysis of these mammalian homologs, however, post a strong barrier due to the high level of overlapping functions. Therefore, the complementary study of Tao in Drosophila midgut and TAOK1/2 in mouse intestine will provide a better understanding of how this conserved pathway mediate mechanosensing to affect intestinal tissue growth. This model has physiological relevance, because human patients recovering from bowel resection, bariatric surgery or radiation therapy have better intestinal growth after solid food intake. Meanwhile, total parenteral nutrition, that is through intravenous supply only, causes intestinal mucosal atrophy. Therefore, interaction between solid food and intestinal epithelium is beneficial, but the mechanism is not well-understood. The genetic studies in Drosophila midgut and in mouse intestine, followed by molecular and protein-protein interaction analyses will unveil their sequence of action of this Tao pathway in transducing mechanical signals for adaptive growth and should provide important insights into similar processes in human intestines.