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

Nature Cell Biology volume 14, pages 401–408 (2012)Cite this article

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Abstract

Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner1,2. Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals3,4. ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation5,6. As ErbB-family ligands and receptors are highly expressed within the stem-cell niche7, 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 family8,9,10, 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 inhibition11,12,13. 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.

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Figure 1: Characterization of Lrig1 expression in the intestine.
Figure 2: Loss of Lrig1 causes crypt expansion.
Figure 3: Loss of Lrig1 causes crypt and stem-cell expansion.
Figure 4: Lrig1 controls endogenous signalling through the ErbB pathway.
Figure 5: Lrig1 controls ErbB activation in vivo.

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Acknowledgements

We thank E. Wagner, M. Frye, S. Yuspa, B. Otto, R. Walker, R. Jeffery, H. Begthel, M. McLeish, the WTCSCR Biofacility and Cambridge Genomics Services for reagents, technical assistance and advice, and R. Fordham and R. Williams for critical comments on the manuscript. We acknowledge support from the UK Medical Research Council and Wellcome Trust.

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Author notes

  1. Richard Poulsom

    Present address: Present address: Centre for Digestive Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK,

  2. Vivian W. Y. Wong, Daniel E. Stange and Mahalia E. Page: These author’s contributed equally to this work

Authors and Affiliations

  1. The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge CB2 0SZ, UK

    Vivian W. Y. Wong, Mahalia E. Page, Matthew W. B. Trotter & Kim B. Jensen

  2. Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK

    Vivian W. Y. Wong, Mahalia E. Page, Agnieszka Wabik, Fiona M. Watt & Kim B. Jensen

  3. Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK

    Vivian W. Y. Wong, Mahalia E. Page & Kim B. Jensen

  4. Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands

    Daniel E. Stange, Marc van de Wetering & Hans Clevers

  5. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK

    Simon Buczacki, Fiona M. Watt & Doug J. Winton

  6. Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka 565-0871, Japan

    Satoshi Itami

  7. Cancer Research UK—London Research Institute, London WC2A 3LY, UK

    Richard Poulsom & Nicholas A. Wright

  8. Barts and the London School of Medicine and Dentistry, London E1 2AD, UK

    Nicholas A. Wright

  9. Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK

    Matthew W. B. Trotter

  10. Celgene Institute Translational Research Europe, Seville E-41092, Spain

    Matthew W. B. Trotter

  11. Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK

    Fiona M. Watt

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  1. Vivian W. Y. Wong
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Contributions

V.W.Y.W., D.E.S., H.C. and K.B.J. participated in the design of the study. K.B.J. wrote the manuscript. V.W.Y.W., D.E.S., M.E.P., S.B., A.W., M.v.d.W., M.W.B.T. and K.B.J carried out experiments. S.I. and F.M.W. provided reagents. V.W.Y.W., D.E.S., M.E.P., F.M.W., M.W.B.T., D.J.W. and H.C. commented on the manuscript. D.E.S., S.B., R.P., N.A.W., D.J.W., H.C. and K.B.J provided conceptual advice on study design and the interpretation of results.

Corresponding authors

Correspondence to Richard Poulsom or Kim B. Jensen.

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Wong, V., Stange, D., Page, M. et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol 14, 401–408 (2012). https://doi.org/10.1038/ncb2464

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