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Cited by 656Wnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene RegulationHedgehog Signaling Pathway Studies

The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

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de Lau, Wim, Peng, Weng Chuan, Gros, Piet, Clevers, Hans·2014·Genes & Development
DOI 10.1101/gad.235473.113PMC PMC3937510
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Abstract

Lgr5 was originally discovered as a common Wnt target gene in adult intestinal crypts and colon cancer. It was subsequently identified as an exquisite marker of multiple Wnt-driven adult stem cell types. Lgr5 and its homologs, Lgr4 and Lgr6, constitute the receptors for R-spondins, potent Wnt signal enhancers and stem cell growth factors. The Lgr5/R-spondin complex acts by neutralizing Rnf43 and Znrf3, two transmembrane E3 ligases that remove Wnt receptors from the stem cell surface. Rnf43/Znrf3 are themselves encoded by Wnt target genes and constitute a negative Wnt feedback loop. Thus, adult stem cells are controlled by an intricate interplay of potent Wnt agonists, antagonists, and anti-antagonists.

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  1. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, 2007 Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003– 1007 17934449
  2. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, 2010 Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6: 25– 36 20085740
  3. Barker N, Rookmaaker MB, Kujala P, Ng A, Leushacke M, Snippert H, van de Wetering M, Tan S, van Es JH, Huch M 2012 Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development. Cell Reports 2: 540– 552 22999937
  4. Bell SM, Schreiner CM, Wert SE, Mucenski ML, Scott WJ, Whitsett JA 2008 R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development 135: 1049– 1058 18256198
  5. Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, Zhou M, Leung JM, Liu Y, Lomas WE 3rd, Dixon M, 2007 R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci 104: 14700– 14705 17804805 PMC1965484
  6. Blaydon DC, Ishii Y, O'Toole EA, Unsworth HC, Teh MT, Ruschendorf F, Sinclair C, Hopsu-Havu VK, Tidman N, Moss C, 2006 The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nat Genet 38: 1245– 1247 17041604
  7. Borycki AG, Emerson CP Jr 2000 Study of skeletal myogenesis in cultures of unsegmented paraxial mesoderm. Methods Mol Biol 137: 351– 357 10948550
  8. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q 2011 R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proc Natl Acad Sci 108: 11452– 11457 21693646 PMC3136304
  9. Chen PH, Chen X, Lin Z, Fang D, He X 2013 The structural basis of R-spondin recognition by LGR5 and RNF43. Genes Dev 27: 1345– 1350 23756651 PMC3701190
  10. Cheng H, Leblond CP 1974 Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 141: 537– 561 4440635
  11. Cheng Y, Kawamura K, Takae S, Deguchi M, Yang Q, Kuo C, Hsueh AJ 2013 Oocyte-derived R-spondin2 promotes ovarian follicle development. FASEB J 27: 2175– 2184 23407710 PMC3659360
  12. Clevers H 2013 The intestinal crypt, a prototype stem cell compartment. Cell 154: 274– 284 23870119
  13. Cossu G, Borello U 1999 Wnt signaling and the activation of myogenesis in mammals. EMBO J 18: 6867– 6872 10601008 PMC1171749
  14. Cruciat CM, Niehrs C 2013 Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol 5: a015081 23085770 PMC3578365
  15. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, 2011 Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476: 293– 297 21727895
  16. de Lau WB, Snel B, Clevers HC 2012 The R-spondin protein family. Genome Biol 13: 242 22439850 PMC3439965
  17. Deng C, Reddy P, Cheng Y, Luo CW, Hsiao CL, Hsueh AJ 2013 Multi-functional norrin is a ligand for the LGR4 receptor. J Cell Sci 126: 2060– 2068 23444378 PMC3666258
  18. de Visser KE, Ciampricotti M, Michalak EM, Tan DW, Speksnijder EN, Hau CS, Clevers H, Barker N, Jonkers J 2012 Developmental stage-specific contribution of LGR5+ cells to basal and luminal epithelial lineages in the postnatal mammary gland. J Pathol 228: 300– 309 22926799
  19. Fevr T, Robine S, Louvard D, Huelsken J 2007 Wnt/β-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol 27: 7551– 7559 17785439 PMC2169070
  20. Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M, Shibata N, Shimizu K, Kamatani N, Shiratori K 2011 Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Scientific reports 1: 161 22355676 PMC3240977
  21. Garrett TP, McKern NM, Lou M, Frenkel MJ, Bentley JD, Lovrecz GO, Elleman TC, Cosgrove LJ, Ward CW 1998 Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor. Nature 394: 395– 399 9690478
  22. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C 1998 Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391: 357– 362 9450748
  23. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C 2011 LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep 12: 1055– 1061 21909076 PMC3185347
  24. Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, Lei H, Mickanin C, Liu D, Ruffner H, 2012 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485: 195– 200 22575959
  25. Hoshii T, Takeo T, Nakagata N, Takeya M, Araki K, Yamamura K 2007 LGR4 regulates the postnatal development and integrity of male reproductive tracts in mice. Biol Reprod 76: 303– 313 17079737
  26. Hsu SY, Semyonov J, Park JI, Chang CL 2005 Evolution of the signaling system in relaxin-family peptides. Ann N Y Acad Sci 1041: 520– 529 15956755
  27. Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, 2013a Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J 32: 2708– 2721 24045232 PMC3801438
  28. Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, 2013b In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494: 247– 250 23354049 PMC3634804
  29. Ireland H, Kemp R, Houghton C, Howard L, Clarke AR, Sansom OJ, Winton DJ 2004 Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: Effect of loss of β-catenin. Gastroenterology 126: 1236– 1246 15131783
  30. Ishikawa T, Tamai Y, Zorn AM, Yoshida H, Seldin MF, Nishikawa S, Taketo MM 2001 Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. Development 128: 25– 33 11092808
  31. Ivanov I, Lo KC, Hawthorn L, Cowell JK, Ionov Y 2007 Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. Oncogene 26: 2873– 2884 17086209
  32. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, 2013 Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci 110: 12649– 12654 23847203 PMC3732970
  33. Jin C, Yin F, Lin M, Li H, Wang Z, Weng J, Liu M, Da Dong X, Qu J, Tu L 2008 GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest Ophthalmol Vis Sci 49: 4245– 4253 18487371
  34. Kamata T, Katsube K, Michikawa M, Yamada M, Takada S, Mizusawa H 2004 R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants. Biochim Biophys Acta 1676: 51– 62 14732490
  35. Kashimada K, Koopman P 2010 Sry: The master switch in mammalian sex determination. Development 137: 3921– 3930 21062860
  36. Kato S, Matsubara M, Matsuo T, Mohri Y, Kazama I, Hatano R, Umezawa A, Nishimori K 2006 Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice. Nephron, Exp Nephrol 104: e63– e75 16785743
  37. Kato S, Mohri Y, Matsuo T, Ogawa E, Umezawa A, Okuyama R, Nishimori K 2007 Eye-open at birth phenotype with reduced keratinocyte motility in LGR4 null mice. FEBS Lett 581: 4685– 4690 17850793
  38. Kazanskaya O, Glinka A, del Barco Barrantes I, Stannek P, Niehrs C, Wu W 2004 R-Spondin2 is a secreted activator of Wnt/β-catenin signaling and is required for Xenopus myogenesis. Dev Cell 7: 525– 534 15469841
  39. Khan TN, Klar J, Nawaz S, Jameel M, Tariq M, Malik NA, Baig SM, Dahl N 2012 Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I). BMC Med Genet 13: 120 23234511 PMC3532313
  40. Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, 2005 Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 309: 1256– 1259 16109882
  41. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, 2012 Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488: 665– 669 22895187
  42. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H 1997 Constitutive transcriptional activation by a β-catenin–Tcf complex in APC−/− colon carcinoma. Science 275: 1784– 1787 9065401
  43. Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H 1998 Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19: 379– 383 9697701
  44. Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J, Nusse R, Kuo CJ 2004 Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci 101: 266– 271 14695885 PMC314174
  45. Leblond CP, Stevens CE 1948 The constant renewal of the intestinal epithelium in the albino rat. Anat Rec 100: 357– 377 18906253
  46. Li XY, Lu Y, Sun HY, Wang JQ, Yang J, Zhang HJ, Fan NG, Xu J, Jiang JJ, Liu RY, 2010 G protein-coupled receptor 48 upregulates estrogen receptor α expression via cAMP/PKA signaling in the male reproductive tract. Development 137: 151– 157 20023170
  47. Lineberry N, Su L, Soares L, Fathman CG 2008 The single subunit transmembrane E3 ligase gene related to anergy in lymphocytes (GRAIL) captures and then ubiquitinates transmembrane proteins across the cell membrane. J Biol Chem 283: 28497– 28505 18713730 PMC2568916
  48. Luo CW, Dewey EM, Sudo S, Ewer J, Hsu SY, Honegger HW, Hsueh AJ 2005 Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor LGR2. Proc Natl Acad Sci 102: 2820– 2825 15703293 PMC549504
  49. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, 2009 Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development 136: 2747– 2756 19605502 PMC2730404
  50. Luo W, Rodriguez M, Valdez JM, Zhu X, Tan K, Li D, Siwko S, Xin L, Liu M 2013 Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells 31: 2492– 2505 23897697 PMC3934101
  51. Marshman E, Booth C, Potten CS 2002 The intestinal epithelial stem cell. BioEssays 24: 91– 98 11782954
  52. Mazerbourg S, Bouley DM, Sudo S, Klein CA, Zhang JV, Kawamura K, Goodrich LV, Rayburn H, Tessier-Lavigne M, Hsueh AJ 2004 Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol 18: 2241– 2254 15192078
  53. McClanahan T, Koseoglu S, Smith K, Grein J, Gustafson E, Black S, Kirschmeier P, Samatar AA 2006 Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol Ther 5: 419– 426 16575208
  54. Moad HE, Pioszak AA 2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 52: 7295– 7304 24050775 PMC3836688
  55. Moffat LL, Robinson RE, Bakoulis A, Clark SG 2014 The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans. Development 141: 617– 628 24401370 PMC3899816
  56. Mohri Y, Kato S, Umezawa A, Okuyama R, Nishimori K 2008 Impaired hair placode formation with reduced expression of hair follicle-related genes in mice lacking Lgr4. Dev Dyn 237: 2235– 2242 18651655
  57. Mohri Y, Umezu T, Hidema S, Tomisawa H, Akamatsu A, Kato S, Nawa A, Nishimori K 2010 Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Fertil Steril 94: 2878– 2881 20638054
  58. Mohri Y, Oyama K, Akamatsu A, Kato S, Nishimori K 2011 Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. Dev Dyn 240: 1626– 1634 21523854
  59. Monkley SJ, Delaney SJ, Pennisi DJ, Christiansen JH, Wainwright BJ 1996 Targeted disruption of the Wnt2 gene results in placentation defects. Development 122: 3343– 3353 8951051
  60. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW 1997 Activation of β-catenin–Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275: 1787– 1790 9065402
  61. Morita H, Mazerbourg S, Bouley DM, Luo CW, Kawamura K, Kuwabara Y, Baribault H, Tian H, Hsueh AJ 2004 Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol 24: 9736– 9743 15509778 PMC525477
  62. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P 1995 Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci 92: 3046– 3050 7708772 PMC42356
  63. Nam JS, Turcotte TJ, Smith PF, Choi S, Yoon JK 2006 Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate β-catenin-dependent gene expression. J Biol Chem 281: 13247– 13257 16543246
  64. Nam JS, Park E, Turcotte TJ, Palencia S, Zhan X, Lee J, Yun K, Funk WD, Yoon JK 2007a Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol 311: 124– 135 17904116 PMC2692258
  65. Nam JS, Turcotte TJ, Yoon JK 2007b Dynamic expression of R-spondin family genes in mouse development. Gene Expr Patterns 7: 306– 312 17035101
  66. Nusse R 2012 Wnt signaling. Cold Spring Harb Perspect Biol 4: a011163 22550232 PMC3331700
  67. Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, 2002 Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110: 775– 787 12297050
  68. Ohkawara B, Glinka A, Niehrs C 2011 Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Dev Cell 20: 303– 314 21397842
  69. Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W, McPherson JR, Allen GE, Ng CC, Wong BH, 2012 Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet 44: 690– 693 22561520
  70. Oyama K, Mohri Y, Sone M, Nawa A, Nishimori K 2011 Conditional knockout of Lgr4 leads to impaired ductal elongation and branching morphogenesis in mouse mammary glands. Sex Dev 5: 205– 212 21791950
  71. Park JI, Semyonov J, Chang CL, Hsu SY 2005 Conservation of the heterodimeric glycoprotein hormone subunit family proteins and the LGR signaling system from nematodes to humans. Endocrine 26: 267– 276 16034181
  72. Parma P, Radi O, Vidal V, Chaboissier MC, Dellambra E, Valentini S, Guerra L, Schedl A, Camerino G 2006 R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 38: 1304– 1309 17041600
  73. Peng WC, de Lau W, Forneris F, Granneman JC, Huch M, Clevers H, Gros P 2013a Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. Cell reports 3: 1885– 1892 23809763
  74. Peng WC, de Lau W, Madoori PK, Forneris F, Granneman JC, Clevers H, Gros P 2013b Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PLoS ONE 8: e83110 24349440 PMC3861454
  75. Pinto D, Gregorieff A, Begthel H, Clevers H 2003 Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17: 1709– 1713 12865297 PMC196179
  76. Plaks V, Brenot A, Lawson DA, Linnemann JR, Van Kappel EC, Wong KC, de Sauvage F, Klein OD, Werb Z 2013 Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell reports 3: 70– 78 23352663 PMC3563842
  77. Qian Y, Liu S, Guan Y, Pan H, Guan X, Qiu Z, Li L, Gao N, Zhao Y, Li X, 2013 Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis. Development 140: 1751– 1761 23533175
  78. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P 1993 Association of the APC gene product with β-catenin. Science 262: 1731– 1734 8259518
  79. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P 1997 Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275: 1790– 1792 9065403
  80. Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A, Zietzling S, Beck V, Therier M, Isken A, 2012 R-spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE 7: e40976 22815884 PMC3397969
  81. Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, Bowtell DD, Gorringe KL, Campbell IG 2013 RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J Pathol 229: 469– 476 23096461
  82. Sato T, Clevers H 2013 Growing self-organizing mini-guts from a single intestinal stem cell: Mechanism and applications. Science 340: 1190– 1194 23744940
  83. Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, Chaudhuri S, Guan Y, Janakiraman V, Jaiswal BS, 2012 Recurrent R-spondin fusions in colon cancer. Nature 488: 660– 664 22895193 PMC3690621
  84. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, van de Wetering M, van den Born M, Begthel H, Vries RG, 2010 Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327: 1385– 1389 20223988
  85. Sone M, Oyama K, Mohri Y, Hayashi R, Clevers H, Nishimori K 2013 LGR4 expressed in uterine epithelium is necessary for uterine gland development and contributes to decidualization in mice. FASEB J 27: 4917– 4928 23975934
  86. Song H, Luo J, Luo W, Weng J, Wang Z, Li B, Li D, Liu M 2008 Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem 283: 36687– 36697 18955481 PMC2605983
  87. Styrkarsdottir U, Thorleifsson G, Sulem P, Gudbjartsson DF, Sigurdsson A, Jonasdottir A, Oddsson A, Helgason A, Magnusson OT, Walters GB, 2013 Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497: 517– 520 23644456
  88. Su LK, Johnson KA, Smith KJ, Hill DE, Vogelstein B, Kinzler KW 1993 Association between wild type and mutant APC gene products. Cancer Res 53: 2728– 2731 8389242
  89. Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, Watanabe W, Ishiko A, Amagai M, Nishikawa T, Sakamoto M 2008 G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am J Pathol 173: 835– 843 18688030 PMC2527081
  90. Tomizuka K, Horikoshi K, Kitada R, Sugawara Y, Iba Y, Kojima A, Yoshitome A, Yamawaki K, Amagai M, Inoue A, 2008 R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum Mol Genet 17: 1278– 1291 18250097
  91. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP 1999 Female development in mammals is regulated by Wnt-4 signalling. Nature 397: 405– 409 9989404
  92. Van der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, Van Gijn ME, Suijkerbuijk S, van de Wetering M, Marra G, 2007 The intestinal Wnt/TCF signature. Gastroenterology 132: 628– 632 17320548
  93. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, 2002 The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111: 241– 250 12408868
  94. van Es JH, Haegebarth A, Kujala P, Itzkovitz S, Koo BK, Boj SF, Korving J, van den Born M, van Oudenaarden A, Robine S, 2012 A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal. Mol Cell Biol 32: 1918– 1927 22393260 PMC3347420
  95. Van Hiel MB, Vandersmissen HP, Van Loy T, Vanden Broeck J 2012 An evolutionary comparison of leucine-rich repeat containing G protein-coupled receptors reveals a novel LGR subtype. Peptides 34: 193– 200 22100731
  96. Van Loy T, Vandersmissen HP, Van Hiel MB, Poels J, Verlinden H, Badisco L, Vassart G, Vanden Broeck J 2008 Comparative genomics of leucine-rich repeats containing G protein-coupled receptors and their ligands. Gen Comp Endocrinol 155: 14– 21 17706217
  97. Van Schoore G, Mendive F, Pochet R, Vassart G 2005 Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol 124: 35– 50 16028069
  98. van Tuyl M, Liu J, Groenman F, Ridsdale R, Han RN, Venkatesh V, Tibboel D, Post M 2006 Iroquois genes influence proximo–distal morphogenesis during rat lung development. Am J Physiol Lung Cell Mol Physiol 290: L777– L789 16299054
  99. Vilella AJ, Severin J, Ureta-Vidal A, Heng L, Durbin R, Birney E 2009 EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates. Genome Res 19: 327– 335 19029536 PMC2652215
  100. Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X 2013a Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev 27: 1339– 1344 23756652 PMC3701189
  101. Wang J, Liu R, Wang F, Hong J, Li X, Chen M, Ke Y, Zhang X, Ma Q, Wang R, 2013b Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 15: 1455– 1463 24212090
  102. Wang Y, Dong J, Li D, Lai L, Siwko S, Li Y, Liu M 2013c Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2. Stem Cells 31: 1921– 1931 23712846 PMC3934111
  103. Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X 2007 R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. J Biol Chem 282: 15903– 15911 17400545
  104. Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, Tu L, Ai D, Li D, Wang J, 2008 Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci 105: 6081– 6086 18424556 PMC2329706
  105. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, 2011 Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci 108: 21188– 21193 22158988 PMC3248495
  106. Xie Y, Zamponi R, Charlat O, Ramones M, Swalley S, Jiang X, Rivera D, Tschantz W, Lu B, Quinn L, 2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO Rep 14: 1120– 1126 24165923 PMC3981092
  107. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, 2004 Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 116: 883– 895 15035989
  108. Xu K, Xu Y, Rajashankar KR, Robev D, Nikolov DB 2013 Crystal structures of Lgr4 and its complex with R-spondin1. Structure 21: 1683– 1689 23891289 PMC3777832
  109. Yamamoto Y, Sakamoto M, Fujii G, Tsuiji H, Kenetaka K, Asaka M, Hirohashi S 2003 Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with β-catenin mutations. Hepatology 37: 528– 533 12601349
  110. Yamashita R, Takegawa Y, Sakumoto M, Nakahara M, Kawazu H, Hoshii T, Araki K, Yokouchi Y, Yamamura K 2009 Defective development of the gall bladder and cystic duct in Lgr4− hypomorphic mice. Dev Dyn 238: 993– 1000 19301403
  111. Yi J, Xiong W, Gong X, Bellister S, Ellis LM, Liu Q 2013 Analysis of LGR4 receptor distribution in human and mouse tissues. PLoS ONE 8: e78144 24205130 PMC3804454
  112. Zebisch M, Xu Y, Krastev C, Macdonald BT, Chen M, Gilbert RJ, He X, Jones EY 2013 Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat Commun 4: 2787 24225776 PMC3905715
  113. Zou Y, Wang F, Liu FY, Huang MZ, Li W, Yuan XQ, Huang OP, He M 2013 RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer. Gene 531: 112– 116 24001777
  114. Zucman-Rossi J, Benhamouche S, Godard C, Boyault S, Grimber G, Balabaud C, Cunha AS, Bioulac-Sage P, Perret C 2007 Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas. Oncogene 26: 774– 780 16964294

Cited by

Sorted by citations

Authors
de Lau, W., Peng, W. C., Gros, P., & Clevers, H.
Affiliations
  • Utrecht University (NL)
  • Royal Netherlands Academy of Arts and Sciences (NL)
Corresponding author
Clevers, Hans
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2014-02-14
Volume
28
Issue
4
Pages
305-316
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.235473.113
PMC
PMC3937510
OpenAlex
W2155040292
Cited by
656
References
3
Citations by year
2026: 45 · 2025: 47 · 2024: 48 · 2023: 44 · 2022: 63 · 2021: 74 · 2020: 73 · 2019: 61 · 2018: 57 · 2017: 54 · 2016: 46 · 2015: 34 · 2014: 9 · 2013: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • European Commission (601876)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (01.80.104.00)
  • FP7 Ideas: European Research Council (232814)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
R-spondin, Lgr5, LGR4, LGR6, RNF43, ZNRF3, Wnt signaling, E3 ubiquitin ligase, negative feedback loop, adult stem cells, intestinal crypts, colon cancer, Wnt antagonists
MeSH terms
Animals, Gene Expression Regulation, Humans, Signal Transduction, Thrombospondins, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, Embryonic Development, Wnt Signaling Pathway

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