Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Blanpain, C., Horsley, V. & Fuchs, E. Epithelial stem cells: turning over new leaves. Cell 128, 445–458 (2007).

    Article  CAS  Google Scholar 

  2. Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

    Article  CAS  Google Scholar 

  3. Li, L. & Clevers, H. Coexistence of quiescent and active adult stem cells in mammals. Science 327, 542–545 (2010).

    Article  CAS  Google Scholar 

  4. Voog, J. & Jones, D. L. Stem cells and the niche: a dynamic duo. Cell. Stem. Cell 6, 103–115 (2010).

    Article  CAS  Google Scholar 

  5. Lee, D. et al. Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. J. Clin. Invest. 119, 2702–2713 (2009).

    Article  CAS  Google Scholar 

  6. Roberts, R. B. et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc. Natl Acad. Sci. USA 99, 1521–1526 (2002).

    Article  CAS  Google Scholar 

  7. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    Article  CAS  Google Scholar 

  8. Gur, G. et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 23, 3270–3281 (2004).

    Article  CAS  Google Scholar 

  9. Jensen, K. B. & Watt, F. M. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc. Natl Acad. Sci. USA 103, 11958–11963 (2006).

    Article  CAS  Google Scholar 

  10. Laederich, M. B. et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J. Biol. Chem. 279, 47050–47056 (2004).

    Article  CAS  Google Scholar 

  11. Haramis, A. P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).

    Article  CAS  Google Scholar 

  12. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383 (1998).

    Article  CAS  Google Scholar 

  13. Van Es, J. H. et al. Notch/ γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).

    Article  CAS  Google Scholar 

  14. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  Google Scholar 

  15. Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  CAS  Google Scholar 

  16. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    Article  CAS  Google Scholar 

  17. Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    Article  CAS  Google Scholar 

  18. Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).

    Article  CAS  Google Scholar 

  19. Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).

    Article  CAS  Google Scholar 

  20. Jensen, K. B. et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell. Stem. Cell 4, 427–439 (2009).

    Article  CAS  Google Scholar 

  21. von Furstenberg, R. J. et al. Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am. J. Physiol. Gastrointest Liver Physiol. 300, G409–G417 (2011).

    Article  CAS  Google Scholar 

  22. Van der Flier, L. G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009).

    Article  CAS  Google Scholar 

  23. Suzuki, Y. et al. Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett 521, 67–71 (2002).

    Article  CAS  Google Scholar 

  24. Schmidt, G. H., Winton, D. J. & Ponder, B. A. Development of the pattern of cell renewal in the crypt–villus unit of chimaeric mouse small intestine. Development 103, 785–790 (1988).

    CAS  PubMed  Google Scholar 

  25. Chong, J. L. et al. E2f1–3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462, 930–934 (2009).

    Article  CAS  Google Scholar 

  26. Van Es, J. H. et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat. Cell Biol. 7, 381–386 (2005).

    Article  CAS  Google Scholar 

  27. Shattuck, D. L. et al. LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy. Mol. Cell Biol. 27, 1934–1946 (2007).

    Article  CAS  Google Scholar 

  28. Ledda, F., Bieraugel, O., Fard, S. S., Vilar, M. & Paratcha, G. Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF. J. Neurosci. 28, 39–49 (2008).

    Article  CAS  Google Scholar 

  29. Citri, A. & Yarden, Y. EGF–ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7, 505–516 (2006).

    Article  CAS  Google Scholar 

  30. Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324 (2010).

    Article  CAS  Google Scholar 

  31. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  Google Scholar 

  32. Luetteke, N. C. et al. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 8, 399–413 (1994).

    Article  CAS  Google Scholar 

  33. Biteau, B. & Jasper, H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138, 1045–1055 (2011).

    Article  CAS  Google Scholar 

  34. Jiang, H., Grenley, M. O., Bravo, M. J., Blumhagen, R. Z. & Edgar, B. A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell. Stem. Cell 8, 84–95 (2011).

    Article  CAS  Google Scholar 

  35. Iyer, R., Thames, H. D., Tealer, J. R., Mason, K. A. & Evans, S. C. Effect of reduced EGFR function on the radiosensitivity and proliferative capacity of mouse jejunal crypt clonogens. Radiother Oncol. 72, 283–289 (2004).

    Article  CAS  Google Scholar 

  36. Jaks, V. et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat. Genet. 40, 1291–1299 (2008).

    Article  CAS  Google Scholar 

  37. Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003).

    Article  Google Scholar 

  38. Smyth, G. K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).

    Article  Google Scholar 

  39. Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA 100, 9440–9445 (2003).

    Article  CAS  Google Scholar 

  40. Gregorieff, A. et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Vivian W. Y. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel E. Stange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahalia E. Page
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon Buczacki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Agnieszka Wabik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Itami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc van de Wetering
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard Poulsom
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nicholas A. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthew W. B. Trotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fiona M. Watt
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Doug J. Winton
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hans Clevers
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kim B. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1553 kb)

Supplementary Table 1

Supplementary Information (XLS 1105 kb)

Supplementary Table 2

Supplementary Information (XLS 694 kb)

Supplementary Table 3

Supplementary Information (XLS 146 kb)

Supplementary Table 4

Supplementary Information (XLS 142 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2464

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing