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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Vivian W. Y. Wong - , University of Cambridge (Author)
  • Daniel E. Stange - , Department of Visceral, Thoracic and Vascular Surgery, Royal Netherlands Academy of Arts and Sciences, Hubrecht Inst, Utrecht University (Author)
  • Mahalia E. Page - , University of Cambridge (Author)
  • Simon Buczacki - , Cancer Research UK Cambridge Institute (CRUK) (Author)
  • Agnieszka Wabik - , University of Cambridge (Author)
  • Satoshi Itami - , Osaka Medical and Pharmaceutical University (Author)
  • Marc van de Wetering - , Royal Netherlands Academy of Arts and Sciences, Utrecht University (Author)
  • Richard Poulsom - , German Cancer Research Center (DKFZ) (Author)
  • Nicholas A. Wright - , German Cancer Research Center (DKFZ), Birkbeck University of London (Author)
  • Matthew W. B. Trotter - , University of Cambridge (Author)
  • Fiona M. Watt - , University of Cambridge, Cancer Research UK Cambridge Institute (CRUK) (Author)
  • Doug J. Winton - , Cancer Research UK Cambridge Institute (CRUK) (Author)
  • Hans Clevers - , Royal Netherlands Academy of Arts and Sciences, Utrecht University (Author)
  • Kim B. Jensen - , University of Cambridge (Author)

Abstract

Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner(1,2). Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals(3,4). ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation(5,6). As ErbB-family ligands and receptors are highly expressed within the stem-cell niche(7), 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(8-10), 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(11-13). 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.

Details

Original languageEnglish
Pages (from-to)401-+
Number of pages16
JournalNature cell biology
Volume14
Issue number4
Publication statusPublished - Apr 2012
Peer-reviewedYes

External IDs

PubMed 22388892
Scopus 84859430024

Keywords

Keywords

  • Receptor tyrosine kinase, Lgr5, Population, Pattern, Maintenance, Inhibition, Adenomas, Niches, Crypts, Level