title: Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling.
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.
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Wong
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Stange
authors.forename: Mahalia E
authors.initials: ME
authors.lastname: Page
authors.forename: Simon
authors.initials: S
authors.lastname: Buczacki
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wabik
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Matthew W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Winton
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Kim B
authors.initials: KB
authors.lastname: Jensen
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D018815:Genes, erbB; D006706:Homeostasis; D007422:Intestines / Q000166:cytology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C101671:Lrig1 protein, mouse