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, P.J.M. Peters, Marc van de Wetering, Daniel E. Stange, Johan E. Es, Daniele Guardavaccaro, Richardus B.M. Schasfoort, Yasuaki Mohri, Katsuhiko Nishimori, Shabaz Mohammed, Albert J.R. Heck, Hans Clevers

Research output: Contribution to journalArticleAcademicpeer-review

699 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)293-297
JournalNature
Volume476
Issue number7360
DOIs
Publication statusPublished - 2011

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Wnt Receptors
Wnt Signaling Pathway
Adult Stem Cells
HEK293 Cells
Gene Deletion
Mass Spectrometry
Gene Expression
Proteins

Keywords

  • METIS-282492
  • IR-79146

Cite this

de Lau, W., Barker, N., Low, T. Y., Koo, B-K., Li, V. S. W., Teunissen, H., ... Clevers, H. (2011). Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature, 476(7360), 293-297. https://doi.org/10.1038/nature10337
de Lau, Wim ; Barker, Nick ; Low, Teck Y. ; Koo, Bon-Kyoung ; Li, Vivian S.W. ; Teunissen, Hans ; Kujala, Pekka ; Haegebarth, Andrea ; Peters, P.J.M. ; van de Wetering, Marc ; Stange, Daniel E. ; Es, Johan E. ; Guardavaccaro, Daniele ; Schasfoort, Richardus B.M. ; Mohri, Yasuaki ; Nishimori, Katsuhiko ; Mohammed, Shabaz ; Heck, Albert J.R. ; Clevers, Hans. / Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. In: Nature. 2011 ; Vol. 476, No. 7360. pp. 293-297.
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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.",
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de Lau, W, Barker, N, Low, TY, Koo, B-K, Li, VSW, Teunissen, H, Kujala, P, Haegebarth, A, Peters, PJM, van de Wetering, M, Stange, DE, Es, JE, Guardavaccaro, D, Schasfoort, RBM, Mohri, Y, Nishimori, K, Mohammed, S, Heck, AJR & Clevers, H 2011, 'Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling' Nature, vol. 476, no. 7360, pp. 293-297. https://doi.org/10.1038/nature10337

Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. / de Lau, Wim; Barker, Nick; Low, Teck Y.; Koo, Bon-Kyoung; Li, Vivian S.W.; Teunissen, Hans; Kujala, Pekka; Haegebarth, Andrea; Peters, P.J.M.; van de Wetering, Marc; Stange, Daniel E.; Es, Johan E.; Guardavaccaro, Daniele; Schasfoort, Richardus B.M.; Mohri, Yasuaki; Nishimori, Katsuhiko; Mohammed, Shabaz; Heck, Albert J.R.; Clevers, Hans.

In: Nature, Vol. 476, No. 7360, 2011, p. 293-297.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

AU - de Lau, Wim

AU - Barker, Nick

AU - Low, Teck Y.

AU - Koo, Bon-Kyoung

AU - Li, Vivian S.W.

AU - Teunissen, Hans

AU - Kujala, Pekka

AU - Haegebarth, Andrea

AU - Peters, P.J.M.

AU - van de Wetering, Marc

AU - Stange, Daniel E.

AU - Es, Johan E.

AU - Guardavaccaro, Daniele

AU - Schasfoort, Richardus B.M.

AU - Mohri, Yasuaki

AU - Nishimori, Katsuhiko

AU - Mohammed, Shabaz

AU - Heck, Albert J.R.

AU - Clevers, Hans

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - METIS-282492

KW - IR-79146

U2 - 10.1038/nature10337

DO - 10.1038/nature10337

M3 - Article

VL - 476

SP - 293

EP - 297

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7360

ER -

de Lau W, Barker N, Low TY, Koo B-K, Li VSW, Teunissen H et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476(7360):293-297. https://doi.org/10.1038/nature10337