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

279 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
Journal	Nature Cell Biology
Volume	14
Issue number	4
Pages (from-to)	401-8
Number of pages	8
ISSN	1465-7392
DOIs	https://doi.org/10.1038/ncb2464
Publication status	Published - Apr 2012
Externally published	Yes

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

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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), 401-8. https://doi.org/10.1038/ncb2464

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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.",

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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.

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KW - Mice, Knockout

KW - Nerve Tissue Proteins

KW - Receptor, erbB-2

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

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Keywords

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