Title: Flavors of EGFR-Ras signals impacting intestinal homeostasis
Abstract: The intestine is a highly dynamic organ with continuous renewal of the epithelial cell layer. The small intestine can be subdivided into the duodenum, the jejunum, and the ileum where villi and crypts are found (Fig. 1) whereas only crypts are present in colon. In the crypts self-renewal of stem cells and production of progeny occurs under the influence of Wnt signaling.1 Progenitor cells enter the transit-amplifying (T/A) zone where they undergo robust expansion to produce the cell numbers to cover the epithelial surface. At the same time progenitor cells differentiate into multiple different lineages such as adsorptive enterocytes, enteroendocrine cells, and goblet cells. Cells migrate up the villus toward the lumen and undergo apoptosis at the tip of the villus, completing the epithelial renewal cycle (Fig. 1). It is poorly understood how progenitor cells balance proliferation and differentiation. Wnt signaling and self-renewal of stem cells in the bottom of the crypt have been extensively studied.1 Epidermal growth factor receptor (EGFR) signals are thought to be relevant in this dynamic T/A zone and several reports have implied that the EGFR pathway is required for intestinal development and contributes to stem cell maintenance. Mechanistically, it is not understood how the EGFR and its downstream Ras-kinase signals impact intestinal homeostasis.