Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

Nat Cell Biol. 2012 Mar 4;14(4):401-8. doi: 10.1038/ncb2464.

Abstract

Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner. Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals. ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation. As ErbB-family ligands and receptors are highly expressed within the stem-cell niche, 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, 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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Feedback, Physiological
  • Gene Expression Profiling
  • Genes, erbB
  • Homeostasis*
  • Intestines / cytology*
  • Intestines / pathology
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction*
  • Stem Cell Niche
  • Stem Cells / cytology*
  • Stem Cells / metabolism*

Substances

  • Lrig1 protein, mouse
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Receptor, ErbB-2