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


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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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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Authors and Affiliations



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.

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Correspondence to Richard Poulsom or Kim B. Jensen.

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The authors declare no competing financial interests.

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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).

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