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.
authors: Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors: Wim
authors: W
authors: de Lau
authors: Nick
authors: N
authors: Barker
authors: Teck Y
authors: TY
authors: Low
authors: Bon-Kyoung
authors: BK
authors: Koo
authors: Vivian S W
authors: VS
authors: Li
authors: Hans
authors: H
authors: Teunissen
authors: Pekka
authors: P
authors: Kujala
authors: Andrea
authors: A
authors: Haegebarth
authors: Peter J
authors: PJ
authors: Peters
authors: Marc
authors: M
authors: van de Wetering
authors: Daniel E
authors: DE
authors: Stange
authors: Johan E
authors: JE
authors: van Es
authors: Daniele
authors: D
authors: Guardavaccaro
authors: Richard B M
authors: RB
authors: Schasfoort
authors: Yasuaki
authors: Y
authors: Mohri
authors: Katsuhiko
authors: K
authors: Nishimori
authors: Shabaz
authors: S
authors: Mohammed
authors: Albert J R
authors: AJ
authors: Heck
authors: Hans
authors: H
authors: Clevers
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction / Q000235:genetics; D019699:Thrombospondins / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D051157:Frizzled Receptors; C496200:LGR4 protein, mouse; C493597:Lgr5 protein, mouse; C548022:Lgr6 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse