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

W.B.M. de Lau; N. Barker; T.Y. Low; B.K. Koo; V.S. Li; H. Teunissen; P. Kujala; A. Haegebarth; P. Peters; M.L. van de Wetering; D.E. Stange; J.H. van Es; D. Guardavaccaro; R.B. Schasfoort; Y. Mohri; K. Nishimori; S. Mohammed; A. Heck; H. Clevers

doi:10.1038/nature10337

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

W.B.M. de Lau, N. Barker, T.Y. Low, B.K. Koo, V.S. Li, H. Teunissen, P. Kujala, A. Haegebarth, P. Peters, M.L. van de Wetering, D.E. Stange, J.H. van Es, D. Guardavaccaro, R.B. Schasfoort, Y. Mohri, K. Nishimori, S. Mohammed, A. Heck, H. Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

1023 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. [KEYWORDS: Adult Stem Cells/metabolism, Animals, Cells, Cultured, Epithelial Cells/cytology/metabolism, Frizzled Receptors/metabolism, Gene Deletion, HEK293 Cells, Humans, Mice, Protein Binding, Protein Structure, Tertiary, Receptors, G-Protein-Coupled/chemistry/deficiency/genetics/ metabolism, Regeneration, Signal Transduction/genetics, Thrombospondins/ metabolism, Wnt Proteins/genetics/ metabolism, Wnt3 Protein, Wnt3A Protein]

Original language	English
Pages (from-to)	293-297
Journal	Nature
Volume	476
Issue number	7360
DOIs	https://doi.org/10.1038/nature10337
Publication status	Published - 2011

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10.1038/nature10337

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de Lau, W. B. M., Barker, N., Low, T. Y., Koo, B. K., Li, V. S., Teunissen, H., Kujala, P., Haegebarth, A., Peters, P., van de Wetering, M. L., Stange, D. E., van Es, J. H., Guardavaccaro, D., Schasfoort, R. B., Mohri, Y., Nishimori, K., Mohammed, S., Heck, A., & 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

@article{57b0974d1b654afbb26c6584cf0a0d06,

title = "Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling",

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. [KEYWORDS: Adult Stem Cells/metabolism, Animals, Cells, Cultured, Epithelial Cells/cytology/metabolism, Frizzled Receptors/metabolism, Gene Deletion, HEK293 Cells, Humans, Mice, Protein Binding, Protein Structure, Tertiary, Receptors, G-Protein-Coupled/chemistry/deficiency/genetics/ metabolism, Regeneration, Signal Transduction/genetics, Thrombospondins/ metabolism, Wnt Proteins/genetics/ metabolism, Wnt3 Protein, Wnt3A Protein]",

author = "{de Lau}, W.B.M. and N. Barker and T.Y. Low and B.K. Koo and V.S. Li and H. Teunissen and P. Kujala and A. Haegebarth and P. Peters and {van de Wetering}, M.L. and D.E. Stange and {van Es}, J.H. and D. Guardavaccaro and R.B. Schasfoort and Y. Mohri and K. Nishimori and S. Mohammed and A. Heck and H. Clevers",

note = "Reporting year: 2011",

year = "2011",

doi = "10.1038/nature10337",

language = "English",

volume = "476",

pages = "293--297",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7360",

}

de Lau, WBM, Barker, N, Low, TY, Koo, BK, Li, VS, Teunissen, H, Kujala, P, Haegebarth, A, Peters, P, van de Wetering, ML, Stange, DE , van Es, JH, Guardavaccaro, D, Schasfoort, RB, Mohri, Y, Nishimori, K, Mohammed, S, Heck, A & 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

TY - JOUR

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

AU - de Lau, W.B.M.

AU - Barker, N.

AU - Low, T.Y.

AU - Koo, B.K.

AU - Li, V.S.

AU - Teunissen, H.

AU - Kujala, P.

AU - Haegebarth, A.

AU - Peters, P.

AU - van de Wetering, M.L.

AU - Stange, D.E.

AU - van Es, J.H.

AU - Guardavaccaro, D.

AU - Schasfoort, R.B.

AU - Mohri, Y.

AU - Nishimori, K.

AU - Mohammed, S.

AU - Heck, A.

AU - Clevers, H.

N1 - Reporting year: 2011

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. [KEYWORDS: Adult Stem Cells/metabolism, Animals, Cells, Cultured, Epithelial Cells/cytology/metabolism, Frizzled Receptors/metabolism, Gene Deletion, HEK293 Cells, Humans, Mice, Protein Binding, Protein Structure, Tertiary, Receptors, G-Protein-Coupled/chemistry/deficiency/genetics/ metabolism, Regeneration, Signal Transduction/genetics, Thrombospondins/ metabolism, Wnt Proteins/genetics/ metabolism, Wnt3 Protein, Wnt3A Protein]

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. [KEYWORDS: Adult Stem Cells/metabolism, Animals, Cells, Cultured, Epithelial Cells/cytology/metabolism, Frizzled Receptors/metabolism, Gene Deletion, HEK293 Cells, Humans, Mice, Protein Binding, Protein Structure, Tertiary, Receptors, G-Protein-Coupled/chemistry/deficiency/genetics/ metabolism, Regeneration, Signal Transduction/genetics, Thrombospondins/ metabolism, Wnt Proteins/genetics/ metabolism, Wnt3 Protein, Wnt3A Protein]

U2 - 10.1038/nature10337

DO - 10.1038/nature10337

M3 - Article

SN - 0028-0836

VL - 476

SP - 293

EP - 297

JO - Nature

JF - Nature

IS - 7360

ER -

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

Abstract

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