Notch pathway regulation of gastrointestinal stem cells

Epithelial cells in the gastrointestinal tract are replenished continuously throughout life from adult stem cells. Stem cell number, proliferation and differentiation are actively regulated to maintain cellular homeostasis. My laboratory is focusing on the role of the Notch pathway to regulate stem cells in the stomach and intestine. We have used pharmacological and genetic approaches to manipulate Notch signalling in mouse models and organoid cultures to test the consequences of pathway inhibition or activation on stem cell function. These studies have demonstrated that Notch governs the balance of epithelial cell proliferation versus differentiation to maintain gastrointestinal tissue homeostasis. Our studies of the intestine have focused on the importance of Notch signalling to maintain active stem cells and to regulate cell fate choice between absorptive (enterocyte) and secretory (goblet, endocrine, Paneth) cell lineages. Notably we have defined the critical functions of the downstream transcription factors ATOH1 and NEUROG3 to induce secretory and endocrine cell differentiation, respectively. We have shown that Notch pathway inhibition results in the rapid loss of LGR5+ stem cells in the intestine, demonstrating the importance of this signalling pathway for stem cell maintenance. In the stomach, we have demonstrated that constitutive Notch activation in gastric stem cells increase stem cell proliferation and, strikingly, led to gland fission and tissue expansion with eventual polyp formation. These observations predict that pathway dysregulation would be associated with gastric tumorigenesis. Accordingly, human gastric cancers show increased expression of Notch pathway components and target genes. Together our studies demonstrate that Notch signalling plays a major role in gastrointestinal tissues to regulate stem cell function and that constitutive pathway activation may be an important driver for gastrointestinal cancers.