The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.
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.
Pubmed ID: 22464327 RIS Download
Adenoma | Adenomatous Polyposis Coli Protein | Animals | Colon | Gene Expression Profiling | Genes, Tumor Suppressor | Humans | Intestinal Neoplasms | Intestine, Small | Membrane Glycoproteins | Mice | Nerve Tissue Proteins | Receptor, Epidermal Growth Factor | Receptors, G-Protein-Coupled | Signal Transduction | Stem Cells