Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

Wim de Lau, Nick Barker, Teck Y. Low, Bon-Kyoung Koo, Vivian S. W. Li, Hans Teunissen, Pekka Kujala, Andrea Haegebarth, Peter J. Peters, Marc van de Wetering, D. E. Stange, J. van Es, Daniele Guardavaccaro, Richard B. M. Schasfoort, Yasuaki Mohri, Katsuhiko Nishimori, Shabaz Mohammed, Albert J. R. Heck and Hans Clevers ()
Additional contact information
Wim de Lau: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Nick Barker: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Teck Y. Low: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center, Utrecht University, 3584 CH Utrecht, The Netherlands
Bon-Kyoung Koo: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Vivian S. W. Li: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Hans Teunissen: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Pekka Kujala: Antoni van Leeuwenhoek Hospital Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
Andrea Haegebarth: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Peter J. Peters: Antoni van Leeuwenhoek Hospital Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
Marc van de Wetering: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
D. E. Stange: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
J. van Es: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Daniele Guardavaccaro: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Richard B. M. Schasfoort: Medical Cell Biophysics, MIRA institute, University of Twente, 7500 AE Enschede, The Netherlands
Yasuaki Mohri: Tohoku University, 981-8555 Sendai, Miyagi, Japan
Katsuhiko Nishimori: Tohoku University, 981-8555 Sendai, Miyagi, Japan
Shabaz Mohammed: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center, Utrecht University, 3584 CH Utrecht, The Netherlands
Albert J. R. Heck: Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center, Utrecht University, 3584 CH Utrecht, The Netherlands
Hans Clevers: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

Nature, 2011, vol. 476, issue 7360, 293-297

Abstract: Abstract The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.

Date: 2011
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DOI: 10.1038/nature10337

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