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

Author

Listed:
  • 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
    Present addresses: Institute of Medical Biology, 06-06 Immunos, Singapore 138648 (N.B.); Bayer Schering Pharma AG, 13353 Berlin, Germany (A.H.).)

  • 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
    Present addresses: Institute of Medical Biology, 06-06 Immunos, Singapore 138648 (N.B.); Bayer Schering Pharma AG, 13353 Berlin, Germany (A.H.).)

  • 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)

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.

Suggested Citation

  • 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 & Dani, 2011. "Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling," Nature, Nature, vol. 476(7360), pages 293-297, August.
    • Handle: RePEc:nat:nature:v:476:y:2011:i:7360:d:10.1038_nature10337
    DOI: 10.1038/nature10337
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