Notch signaling in the intestinal epithelium (#19)
The epithelium of the small intestine consists of four principal cell types: absorptive enterocytes, mucus secreting goblet cells, antimicrobial Paneth cells, and hormone secreting enteroendocrine cells. While most differentiated cell types reside within the villus, Paneth cells are found at the bottom of the crypt. They are in close contact with the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) and olfactomedin-4 (Olfm4)-expressing intestinal stem cells. These stem cells, also known as crypt base columnar cells (CBCs), proliferate constantly and give rise to transient amplifying (TA) cells, which localize within the crypt compartment just above the Paneth cells. TA cells migrate upwards and differentiate at the crypt-villus boundary in one of the 4 known cell types of the small intestine. These regeneration and differentiation processes have to be under stringent control to ensure proper homeostasis. Notch signaling within the intestinal epithelium is required for the maintenance of proliferating crypt progenitors and the formation of enterocytes. Ablation of Notch signaling results in the loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. Here we aimed at identifying the physiological Notch ligands triggering Notch signaling in crypt progenitor cells and investigated the consequences of loss of Notch signaling for intestinal stem cells. Moreover, we directly investigated whether the transcription factor Klf4 is essential for goblet cell differentiation in Notch signaling deficient mice. Furthermore, we have now demonstrated that the Notch and Wnt signaling pathways cooperate to maintain the integrity of the ISC compartment by co-regulation of a specific signature that includes important stem cell regulators such as Bmi1, CD44, Sox9 and c-myc. Importantly, elimination of Jagged1 in intestinal cancer cells but not in normal cells results in loss of this signature and in a significant reduction of tumor number in the APCMin/+ background.