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Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling

Nature Cell Biology volume 13, pages 1100–1107 (2011)Cite this article

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Abstract

The formation and maintenance of complex organs requires segregation of distinct cell populations into defined territories (that is, cell sorting) and the establishment of boundaries between them. Here we have investigated the mechanism by which Eph/ephrin signalling controls the compartmentalization of cells in epithelial tissues. We show that EphB/ephrin-B signalling in epithelial cells regulates the formation of E-cadherin-based adhesions. EphB receptors interact with E-cadherin and with the metalloproteinase ADAM10 at sites of adhesion and their activation induces shedding of E-cadherin by ADAM10 at interfaces with ephrin-B1-expressing cells. This process results in asymmetric localization of E-cadherin and, as a consequence, in differences in cell affinity between EphB-positive and ephrin-B-positive cells. Furthermore, genetic inhibition of ADAM10 activity in the intestine of mice results in a lack of compartmentalization of Paneth cells within the crypt stem cell niche, a defect that phenocopies that of EphB3-null mice. These results provide important insights into the regulation of cell migration in the intestinal epithelium and may help in the understanding of the nature of the cell sorting process in other epithelial tissues where Eph–ephrin interactions play a central role.

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Figure 1: Asymmetrical E-cadherin distribution downstream of EphB signalling is mediated by metalloproteinase activity.
Figure 2: ADAM metalloproteinases are required for EphB/ephrin-B-mediated cell sorting.
Figure 3: ADAM10 metalloproteinase activity is required for EphB/ephrin-B-mediated cell sorting and E-cadherin remodelling.
Figure 4: ADAM10, EphB2 and E-cadherin form a complex that induces shedding of E-cadherin at sites of EphB–ephrin-B interaction.
Figure 5: Transgenic expression of dominant-negative ADAM10 induces mis-positioning of Paneth cells in the intestinal epithelium.

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Acknowledgements

We thank J. W. Nelson (Stanford University, USA) for the E-cadherin–GFP fusion construct, Z. Werb (University of California, San Francisco, USA) for ADAM10 expression constructs, J. I. Gordon (Washington University, St Louis, USA) for the CR2 expression plasmid, the Advanced Digital Microscopy Facility (ADM-IRB) for support with imaging, the Mouse Mutant Core Facility, X. Hernando and S. Palomo-Ponce for help with generation and maintenance of transgenic mice and all members of the Batlle laboratory for support and useful discussions. This study was supported by grants awarded to E.B. by the European Research Council (ERC) and the Spanish Ministry of Science and Innovation (SAF and Consolider). G.S. was supported by a fellowship from the MICINN and C.C. held a predoctoral fellowship from the department of education from the Generalitat de Catalunya.

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  1. Carme Cortina

    Present address: Present address: Center of Regenerative Medicine in Barcelona (CMRB), Dr. Aiguader, 88, 08003 Barcelona, Spain,

Authors and Affiliations

  1. Oncology program, Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain

    Guiomar Solanas, Carme Cortina, Marta Sevillano & Eduard Batlle

  2. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys, 08010 Barcelona, 23, Spain

    Eduard Batlle

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  1. Guiomar Solanas
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Contributions

G.S., C.C. and E.B designed the experiments, G.S and C.C. carried out and analysed the experiments, M.S. contributed with technical assistance with histology, G.S. and E.B. prepared the manuscript and E.B. set the conceptual framework and supervised the work.

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Correspondence to Carme Cortina or Eduard Batlle.

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The authors declare no competing financial interests.

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Solanas, G., Cortina, C., Sevillano, M. et al. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol 13, 1100–1107 (2011). https://doi.org/10.1038/ncb2298

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