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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 supportĀ 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

Authors

  • Powell AE
  • Wang Y
  • Li Y
  • Poulin EJ
  • Means AL
  • Washington MK
  • Higginbotham JN
  • Juchheim A
  • Prasad N
  • Levy SE
  • Guo Y
  • Shyr Y
  • Aronow BJ
  • Haigis KM
  • Franklin JL
  • Coffey RJ

Journal

Cell

Publication Data

March 30, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA151566
  • Agency: NCI NIH HHS, Id: CA46413
  • Agency: NIDDK NIH HHS, Id: P30 DK043351
  • Agency: NIDDK NIH HHS, Id: P30 DK058404
  • Agency: NCI NIH HHS, Id: P50 CA095103
  • Agency: NCI NIH HHS, Id: P50CA095103
  • Agency: NCI NIH HHS, Id: R01 CA046413
  • Agency: NCI NIH HHS, Id: R01 CA151566
  • Agency: NCI NIH HHS, Id: T32 CA119925
  • Agency: NIGMS NIH HHS, Id: T32 GM008554
  • Agency: NCI NIH HHS, Id: T32CA119925
  • Agency: NIGMS NIH HHS, Id: T32GM008554
  • Agency: NCI NIH HHS, Id: U01 CA084239
  • Agency: NCI NIH HHS, Id: U01CA084239
  • Agency: NCATS NIH HHS, Id: UL1 TR000077

Mesh Terms

  • 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