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

TY - JOUR

T1 - Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

AU - Wong, Vivian W Y

AU - Stange, Daniel E

AU - Page, Mahalia E

AU - Buczacki, Simon

AU - Wabik, Agnieszka

AU - Itami, Satoshi

AU - van de Wetering, Marc

AU - Poulsom, Richard

AU - Wright, Nicholas A

AU - Trotter, Matthew W B

AU - Watt, Fiona M

AU - Winton, Doug J

AU - Clevers, Hans

AU - Jensen, Kim B

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

KW - Animals

KW - Feedback, Physiological

KW - Gene Expression Profiling

KW - Genes, erbB

KW - Homeostasis

KW - Intestines

KW - Membrane Glycoproteins

KW - Mice

KW - Mice, Inbred Strains

KW - Mice, Knockout

KW - Nerve Tissue Proteins

KW - Receptor, erbB-2

KW - Signal Transduction

KW - Stem Cell Niche

KW - Stem Cells

U2 - 10.1038/ncb2464

DO - 10.1038/ncb2464

M3 - Journal article

C2 - 22388892

SN - 1465-7392

VL - 14

SP - 401

EP - 408

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -