The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor
Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de suppresseur de tumeurs joué par Lrig1 dans les cellules souches de l'intestin
Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1+ colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5+ colonic stem cells; genes upregulated in the Lrig1+ population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1+ cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia. º Lrig1, an ErbB negative regulator, marks quiescent intestinal stem cells º Lrig1 and Lgr5 transcriptome profiles are distinct º Loss of APC in Lrig1+ cells results in intestinal adenomas º Functionally null Lrig1 mice develop duodenal adenomas Loss of calibrated EGFR/ErbB signaling in quiescent intestinal stem cells has neoplastic consequences, generating advanced colon adenomas. Although Lrig1+ cells are distinct from proliferating Lgr5+ cells, they are located at the base of the crypt.