title: The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Powell
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yina
authors.initials: Y
authors.lastname: Li
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Poulin
authors.forename: Anna L
authors.initials: AL
authors.lastname: Means
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.forename: James N
authors.initials: JN
authors.lastname: Higginbotham
authors.forename: Alwin
authors.initials: A
authors.lastname: Juchheim
authors.forename: Nripesh
authors.initials: N
authors.lastname: Prasad
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Franklin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D000236:Adenoma / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D007414:Intestinal Neoplasms / Q000473:pathology; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C484445:LRIG1 protein, human; C493597:Lgr5 protein, mouse; C101671:Lrig1 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D066246:ErbB Receptors