Lrigl controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner (1,2). Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals (3,4). ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation (5,6). As ErbB-family ligands and receptors are highly expressed within the stem-cell niche (7), we hypothesize that strong endogenous regulators must control the pathway in the stem-cell compartment. Here we show that Lrig1, a negative-feedback regulator of the ErbB receptor family (8-10), is highly expressed by intestinal stem cells and controls the size of the intestinal stem-cell niche by regulating the amplitude of growth-factor signalling. Intestinal stem-cell maintenance has so far been attributed to a combination of Wnt and Notch activation and Bmpr inhibition (11-13). Our findings reveal ErbB activation as a strong inductive signal for stem-cell proliferation. This has implications for our understanding of ErbB signalling in tissue development and maintenance and the progression of malignant disease.