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

Vivian W Y Wong; Daniel E Stange; Mahalia E Page; Simon Buczacki; Agnieszka Wabik; Satoshi Itami; Marc van de Wetering; Richard Poulsom; Nicholas A Wright; Matthew W B Trotter; Fiona M Watt; Doug J Winton; Hans Clevers; Kim B Jensen

doi:10.1038/ncb2464

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

Vivian W Y Wong, Daniel E Stange, Mahalia E Page, Simon Buczacki, Agnieszka Wabik, Satoshi Itami, Marc van de Wetering, Richard Poulsom, Nicholas A Wright, Matthew W B Trotter, Fiona M Watt, Doug J Winton, Hans Clevers, Kim B Jensen

Gene Therapy and Regenerative Medicine

University of Cambridge

Research output: Contribution to journal › Article › peer-review

349 Citations (Scopus)

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.

Original language	English
Article number	N/A
Pages (from-to)	401-408
Number of pages	8
Journal	Nature Cell Biology
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/ncb2464
Publication status	Published - Apr 2012

Keywords

Animals
Feedback, Physiological
Gene Expression Profiling
Genes, erbB
Homeostasis
Intestines
Membrane Glycoproteins
Mice
Mice, Inbred Strains
Mice, Knockout
Nerve Tissue Proteins
Receptor, erbB-2
Signal Transduction
Stem Cell Niche
Stem Cells

Access to Document

10.1038/ncb2464

Cite this

Wong, V. W. Y., Stange, D. E., Page, M. E., Buczacki, S., Wabik, A., Itami, S., van de Wetering, M., Poulsom, R., Wright, N. A., Trotter, M. W. B., Watt, F. M., Winton, D. J., Clevers, H., & Jensen, K. B. (2012). Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nature Cell Biology, 14(4), 401-408. Article N/A. https://doi.org/10.1038/ncb2464

@article{a5ee836c95144938b6dc521dbbac92bc,

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.",

keywords = "Animals, Feedback, Physiological, Gene Expression Profiling, Genes, erbB, Homeostasis, Intestines, Membrane Glycoproteins, Mice, Mice, Inbred Strains, Mice, Knockout, Nerve Tissue Proteins, Receptor, erbB-2, Signal Transduction, Stem Cell Niche, Stem Cells",

author = "Wong, {Vivian W Y} and Stange, {Daniel E} and Page, {Mahalia E} and Simon Buczacki and Agnieszka Wabik and Satoshi Itami and {van de Wetering}, Marc and Richard Poulsom and Wright, {Nicholas A} and Trotter, {Matthew W B} and Watt, {Fiona M} and Winton, {Doug J} and Hans Clevers and Jensen, {Kim B}",

year = "2012",

month = apr,

doi = "10.1038/ncb2464",

language = "English",

volume = "14",

pages = "401--408",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "4",

}

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 - Article

C2 - 22388892

SN - 1465-7392

VL - 14

SP - 401

EP - 408

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

M1 - N/A

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this