Wnt/β-Catenin Signaling and Disease

The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. The Wnt1 gene, originally named Int-1, was identified in 1982 as a gene activated by integration of mouse mammary tumor virus proviral DNA in virally induced breast tumors (Nusse and Varmus, 1982Nusse R. Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome.Cell. 1982; 31: 99-109Abstract Full Text PDF PubMed Scopus (0) Google Scholar). The Wnt1 proto-oncogene encodes a secreted, cysteine-rich protein. The fly Wingless (wg) gene, which controls segment polarity during larval development (Nüsslein-Volhard and Wieschaus, 1980Nüsslein-Volhard C. Wieschaus E. Mutations affecting segment number and polarity in Drosophila.Nature. 1980; 287: 795-801Crossref PubMed Google Scholar), was later shown to be a homolog of Wnt1 (Rijsewijk et al., 1987Rijsewijk F. Schuermann M. Wagenaar E. Parren P. Weigel D. Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless.Cell. 1987; 50: 649-657Abstract Full Text PDF PubMed Scopus (0) Google Scholar). By 1994, epistasis experiments examining the relationships among segment polarity mutations delineated the core of this developmental signal transduction cascade in Drosophila (e.g., porcupine, dishevelled, armadillo (β-catenin), and zeste-white 3/GSK3 gene (Noordermeer et al., 1994Noordermeer J. Klingensmith J. Perrimon N. Nusse R. dishevelled and armadillo act in the wingless signalling pathway in Drosophila.Nature. 1994; 367: 80-83Crossref PubMed Scopus (0) Google Scholar, Peifer et al., 1994Peifer M. Sweeton D. Casey M. Wieschaus E. wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo.Development. 1994; 120: 369-380PubMed Google Scholar, Siegfried et al., 1992Siegfried E. Chou T.B. Perrimon N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate.Cell. 1992; 71: 1167-1179Abstract Full Text PDF PubMed Scopus (0) Google Scholar). Injection of mouse Wnt1 mRNA into early frog embryos caused a duplication of the body axis in Xenopus, providing an assay to study the Wnt pathway in vertebrates (McMahon and Moon, 1989McMahon A.P. Moon R.T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis.Cell. 1989; 58: 1075-1084Abstract Full Text PDF PubMed Scopus (0) Google Scholar). The combined observations from Drosophila and Xenopus unveiled a highly conserved signaling pathway, commonly referred to as the canonical Wnt cascade. A few years later, major gaps in Wnt signal transduction were closed with the identification of TCF/LEF transcription factors as Wnt nuclear effectors (Behrens et al., 1996Behrens J. von Kries J.P. Kühl M. Bruhn L. Wedlich D. Grosschedl R. Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1.Nature. 1996; 382: 638-642Crossref PubMed Scopus (0) Google Scholar, Molenaar et al., 1996Molenaar M. van de Wetering M. Oosterwegel M. Peterson-Maduro J. Godsave S. Korinek V. Roose J. Destrée O. Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.Cell. 1996; 86: 391-399Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar) and Frizzleds as Wnt receptors (Bhanot et al., 1996Bhanot P. Brink M. Samos C.H. Hsieh J.C. Wang Y. Macke J.P. Andrew D. Nathans J. Nusse R. A new member of the frizzled family from Drosophila functions as a Wingless receptor.Nature. 1996; 382: 225-230Crossref PubMed Scopus (0) Google Scholar), which work together with LRPs/Arrow as coreceptors (Wehrli et al., 2000Wehrli M. Dougan S.T. Caldwell K. O'Keefe L. Schwartz S. Vaizel-Ohayon D. Schejter E. Tomlinson A. DiNardo S. arrow encodes an LDL-receptor-related protein essential for Wingless signalling.Nature. 2000; 407: 527-530Crossref PubMed Scopus (0) Google Scholar). The first direct connection between the Wnt pathway and human disease came in the early 1990s. The adenomatous polyposis coli (APC) gene was discovered independently in a hereditary cancer syndrome termed familial adenomatous polyposis (FAP; Kinzler et al., 1991Kinzler K.W. Nilbert M.C. Su L.K. Vogelstein B. Bryan T.M. Levy D.B. Smith K.J. Preisinger A.C. Hedge P. McKechnie D. et al.Identification of FAP locus genes from chromosome 5q21.Science. 1991; 253: 661-665Crossref PubMed Google Scholar, Nishisho et al., 1991Nishisho I. Nakamura Y. Miyoshi Y. Miki Y. Ando H. Horii A. Koyama K. Utsunomiya J. Baba S. Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.Science. 1991; 253: 665-669Crossref PubMed Google Scholar). Soon thereafter, the large cytoplasmic APC protein was found to interact with β-catenin (Rubinfeld et al., 1993Rubinfeld B. Souza B. Albert I. Müller O. Chamberlain S.H. Masiarz F.R. Munemitsu S. Polakis P. Association of the APC gene product with beta-catenin.Science. 1993; 262: 1731-1734Crossref PubMed Google Scholar, Su et al., 1993Su L.K. Vogelstein B. Kinzler K.W. Association of the APC tumor suppressor protein with catenins.Science. 1993; 262: 1734-1737Crossref PubMed Google Scholar). Many additional pathway components and disease connections were uncovered over the last two decades. Below, we discuss these, taking the reader from Wnt secretion through Wnt reception and signal transduction to the nuclear response of the recipient cell. Most mammalian genomes, including the human genome, harbor 19 Wnt genes, falling into 12 conserved Wnt subfamilies. At least 11 of these subfamilies occur in the genome of a Cnidaria (the sea anemone Nematostella vectensis), emphasizing the crucial role that Wnt proteins play in organismal patterning throughout the animal kingdom (Kusserow et al., 2005Kusserow A. Pang K. Sturm C. Hrouda M. Lentfer J. Schmidt H.A. Technau U. von Haeseler A. Hobmayer B. Martindale M.Q. Holstein T.W. Unexpected complexity of the Wnt gene family in a sea anemone.Nature. 2005; 433: 156-160Crossref PubMed Scopus (0) Google Scholar). Even sponges contain a few Wnt genes, whereas single-cell organisms do not, suggesting that Wnt signaling may have been instrumental in the evolutionary origin of multicellular animals (Petersen and Reddien, 2009Petersen C.P. Reddien P.W. Wnt signaling and the polarity of the primary body axis.Cell. 2009; 139: 1056-1068Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), and mutations of six Wnt genes have been identified in a variety of hereditary conditions (Table 1).Table 1Human Diseases Associated with Mutations of Wnt Pathway Components after MacDonald et al., 2009MacDonald B.T. Tamai K. He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases.Dev. Cell. 2009; 17: 9-26Abstract Full Text Full Text PDF PubMed Scopus (1742) Google Scholar and the Wnt HomepageaWnt homepage, http://wnt.stanford.edu.ProteinMutation Type and Associated Human Disease(s)Key ReferencesPORCNLOF X-linked focal dermal hypoplasiaGrzeschik et al., 2007Grzeschik K.H. Bornholdt D. Oeffner F. König A. del Carmen Boente M. Enders H. Fritz B. Hertl M. Grasshoff U. Höfling K. et al.Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia.Nat. Genet. 2007; 39: 833-835Crossref PubMed Scopus (163) Google Scholar, Wang et al., 2007Wang X. Reid Sutton V. Omar Peraza-Llanes J. Yu Z. Rosetta R. Kou Y.C. Eble T.N. Patel A. Thaller C. Fang P. Van den Veyver I.B. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia.Nat. Genet. 2007; 39: 836-838Crossref PubMed Scopus (151) Google ScholarWNT3LOF tetra-ameliaNiemann et al., 2004Niemann S. Zhao C. Pascu F. Stahl U. Aulepp U. Niswander L. Weber J.L. Müller U. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.Am. J. Hum. Genet. 2004; 74: 558-563Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarWNT4LOF Mullerian duct regression and virilisationBiason-Lauber et al., 2004Biason-Lauber A. Konrad D. Navratil F. Schoenle E.J. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman.N. Engl. J. Med. 2004; 351: 792-798Crossref PubMed Scopus (0) Google ScholarWNT5BLOF? type II diabetesKanazawa et al., 2004Kanazawa A. Tsukada S. Sekine A. Tsunoda T. Takahashi A. Kashiwagi A. Tanaka Y. Babazono T. Matsuda M. Kaku K. et al.Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes.Am. J. Hum. Genet. 2004; 75: 832-843Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarWNT7ALOF Fuhrmann syndromeWoods et al., 2006Woods C.G. Stricker S. Seemann P. Stern R. Cox J. Sherridan E. Roberts E. Springell K. Scott S. Karbani G. et al.Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.Am. J. Hum. Genet. 2006; 79: 402-408Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarWNT10ALOF odonto-onchyo-dermal hypoplasiaAdaimy et al., 2007Adaimy L. Chouery E. Megarbane H. Mroueh S. Delague V. Nicolas E. Belguith H. de Mazancourt P. Megarbane A. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.Am. J. Hum. Genet. 2007; 81: 821-828Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarWNT10BLOF obesityChristodoulides et al., 2006Christodoulides C. Scarda A. Granzotto M. Milan G. Dalla Nora E. Keogh J. De Pergola G. Stirling H. Pannacciulli N. Sethi J.K. et al.WNT10B mutations in human obesity.Diabetologia. 2006; 49: 678-684Crossref PubMed Scopus (0) Google ScholarRSPO1LOF XX sex reversal with palmoplantar hyperkaratosisParma et al., 2006Parma P. Radi O. Vidal V. Chaboissier M.C. Dellambra E. Valentini S. Guerra L. Schedl A. Camerino G. R-spondin1 is essential in sex determination, skin differentiation and malignancy.Nat. Genet. 2006; 38: 1304-1309Crossref PubMed Scopus (0) Google ScholarRSPO4LOF autosomal-recessive anonychia and hyponychia congenitaBlaydon et al., 2006Blaydon D.C. Ishii Y. O'Toole E.A. Unsworth H.C. Teh M.T. Rüschendorf F. Sinclair C. Hopsu-Havu V.K. Tidman N. Moss C. et al.The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia.Nat. Genet. 2006; 38: 1245-1247Crossref PubMed Scopus (0) Google ScholarSOSTLOF high bone mass, sclerosteosis, Van Buchem diseaseBalemans et al., 2001Balemans W. Ebeling M. Patel N. Van Hul E. Olson P. Dioszegi M. Lacza C. Wuyts W. Van Den Ende J. Willems P. et al.Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).Hum. Mol. Genet. 2001; 10: 537-543Crossref PubMed Google Scholar, Brunkow et al., 2001Brunkow M.E. Gardner J.C. Van Ness J. Paeper B.W. Kovacevich B.R. Proll S. Skonier J.E. Zhao L. Sabo P.J. Fu Y. et al.Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein.Am. J. Hum. Genet. 2001; 68: 577-589Abstract Full Text Full Text PDF PubMed Scopus (504) Google ScholarNorrin (NDP)LOF familial exudative vitreoretinopathyXu et al., 2004Xu Q. Wang Y. Dabdoub A. Smallwood P.M. Williams J. Woods C. Kelley M.W. Jiang L. Tasman W. Zhang K. Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.Cell. 2004; 116: 883-895Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarLRP5GOF (alternative splicing) hyperparathyroid tumors, GOF high bone mass, LOF osteoporosis-pseudoglioma, LOF eye vascular defectsBjörklund et al., 2007Björklund P. Akerström G. Westin G. An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling.PLoS Med. 2007; 4: e328Crossref PubMed Scopus (0) Google Scholar, Boyden et al., 2002Boyden L.M. Mao J. Belsky J. Mitzner L. Farhi A. Mitnick M.A. Wu D. Insogna K. Lifton R.P. High bone density due to a mutation in LDL-receptor-related protein 5.N. Engl. J. Med. 2002; 346: 1513-1521Crossref PubMed Scopus (0) Google Scholar, Gong et al., 2001Gong Y. Slee R.B. Fukai N. Rawadi G. Roman-Roman S. Reginato A.M. Wang H. Cundy T. Glorieux F.H. Lev D. et al.Osteoporosis-Pseudoglioma Syndrome Collaborative GroupLDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.Cell. 2001; 107: 513-523Abstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar, Little et al., 2002Little R.D. Carulli J.P. Del Mastro R.G. Dupuis J. Osborne M. Folz C. Manning S.P. Swain P.M. Zhao S.C. Eustace B. et al.A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am. J. Hum. Genet. 2002; 70: 11-19Abstract Full Text Full Text PDF PubMed Scopus (808) Google Scholar, Toomes et al., 2004Toomes C. Bottomley H.M. Jackson R.M. Towns K.V. Scott S. Mackey D.A. Craig J.E. Jiang L. Yang Z. Trembath R. et al.Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.Am. J. Hum. Genet. 2004; 74: 721-730Abstract Full Text Full Text PDF PubMed Scopus (196) Google ScholarLRP6LOF early coronary disease and osteoporosisMani et al., 2007Mani A. Radhakrishnan J. Wang H. Mani A. Mani M.A. Nelson-Williams C. Carew K.S. Mane S. Najmabadi H. Wu D. Lifton R.P. LRP6 mutation in a family with early coronary disease and metabolic risk factors.Science. 2007; 315: 1278-1282Crossref PubMed Scopus (0) Google ScholarFZD4LOF familial exudative vitreoretinopathyRobitaille et al., 2002Robitaille J. MacDonald M.L. Kaykas A. Sheldahl L.C. Zeisler J. Dubé M.P. Zhang L.H. Singaraja R.R. Guernsey D.L. Zheng B. et al.Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.Nat. Genet. 2002; 32: 326-330Crossref PubMed Scopus (264) Google ScholarFZD9LOF Williams-Beuren SyndromeWang et al., 1999Wang Y.K. Spörle R. Paperna T. Schughart K. Francke U. Characterization and expression pattern of the frizzled gene Fzd9, the mouse homolog of FZD9 which is deleted in Williams-Beuren syndrome.Genomics. 1999; 57: 235-248Crossref PubMed Scopus (0) Google ScholarTSPAN12LOF familial exudative vitreoretinopathyNikopoulos et al., 2010Nikopoulos K. Gilissen C. Hoischen A. van Nouhuys C.E. Boonstra F.N. Blokland E.A. Arts P. Wieskamp N. Strom T.M. Ayuso C. et al.Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy.Am. J. Hum. Genet. 2010; 86: 240-247Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Poulter et al., 2010Poulter J.A. Ali M. Gilmour D.F. Rice A. Kondo H. Hayashi K. Mackey D.A. Kearns L.S. Ruddle J.B. Craig J.E. et al.Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy.Am. J. Hum. Genet. 2010; 86: 248-253Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarAPCDD1LOF hereditary hypothrochosis simplexShimomura et al., 2010Shimomura Y. Agalliu D. Vonica A. Luria V. Wajid M. Baumer A. Belli S. Petukhova L. Schinzel A. Brivanlou A.H. et al.APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.Nature. 2010; 464: 1043-1047Crossref PubMed Scopus (0) Google ScholarAxin1LOF caudal duplication, cancerOates et al., 2006Oates N.A. van Vliet J. Duffy D.L. Kroes H.Y. Martin N.G. Boomsma D.I. Campbell M. Coulthard M.G. Whitelaw E. Chong S. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.Am. J. Hum. Genet. 2006; 79: 155-162Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Satoh et al., 2000Satoh S. Daigo Y. Furukawa Y. Kato T. Miwa N. Nishiwaki T. Kawasoe T. Ishiguro H. Fujita M. Tokino T. et al.AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1.Nat. Genet. 2000; 24: 245-250Crossref PubMed Scopus (0) Google ScholarAxin2LOF tooth agenesis, cancerLammi et al., 2004Lammi L. Arte S. Somer M. Jarvinen H. Lahermo P. Thesleff I. Pirinen S. Nieminen P. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.Am. J. Hum. Genet. 2004; 74: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Liu et al., 2000Liu W. Dong X. Mai M. Seelan R.S. Taniguchi K. Krishnadath K.K. Halling K.C. Cunningham J.M. Boardman L.A. Qian C. et al.Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling.Nat. Genet. 2000; 26: 146-147Crossref PubMed Scopus (0) Google ScholarAPCLOF familial adenomatous polyposis, cancerKinzler et al., 1991Kinzler K.W. Nilbert M.C. Su L.K. Vogelstein B. Bryan T.M. Levy D.B. Smith K.J. Preisinger A.C. Hedge P. McKechnie D. et al.Identification of FAP locus genes from chromosome 5q21.Science. 1991; 253: 661-665Crossref PubMed Google Scholar, Nishisho et al., 1991Nishisho I. Nakamura Y. Miyoshi Y. Miki Y. Ando H. Horii A. Koyama K. Utsunomiya J. Baba S. Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.Science. 1991; 253: 665-669Crossref PubMed Google ScholarWTXLOF Wilms tumor, LOF OCTSJenkins et al., 2009Jenkins Z.A. van Kogelenberg M. Morgan T. Jeffs A. Fukuzawa R. Pearl E. Thaller C. Hing A.V. Porteous M.E. Garcia-Miñaur S. et al.Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.Nat. Genet. 2009; 41: 95-100Crossref PubMed Scopus (0) Google Scholar, Major et al., 2007Major M.B. Camp N.D. Berndt J.D. Yi X. Goldenberg S.J. Hubbert C. Biechele T.L. Gingras A.C. Zheng N. Maccoss M.J. et al.Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.Science. 2007; 316: 1043-1046Crossref PubMed Scopus (0) Google Scholar, Rivera et al., 2007Rivera M.N. Kim W.J. Wells J. Driscoll D.R. Brannigan B.W. Han M. Kim J.C. Feinberg A.P. Gerald W.L. Vargas S.O. et al.An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.Science. 2007; 315: 642-645Crossref PubMed Scopus (0) Google Scholarβ-cateninGOF cancerMorin et al., 1997Morin P.J. Sparks A.B. Korinek V. Barker N. Clevers H. Vogelstein B. Kinzler K.W. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Science. 1997; 275: 1787-1790Crossref PubMed Scopus (2848) Google ScholarLEF1LOF sebaceous skin tumorTakeda et al., 2006Takeda H. Lyle S. Lazar A.J. Zouboulis C.C. Smyth I. Watt F.M. Human sebaceous tumors harbor inactivating mutations in LEF1.Nat. Med. 2006; 12: 395-397Crossref PubMed Scopus (0) Google ScholarTCF4GOF type II diabetes, colon cancerBass et al., 2011Bass A.J. Lawrence M.S. Brace L.E. Ramos A.H. Drier Y. Cibulskis K. Sougnez C. Voet D. Saksena G. Sivachenko A. et al.Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.Nat. Genet. 2011; 43: 964-968Crossref PubMed Scopus (169) Google Scholar, Grant et al., 2006Grant S.F. Thorleifsson G. Reynisdottir I. Benediktsson R. Manolescu A. Sainz J. Helgason A. Stefansson H. Emilsson V. Helgadottir A. et al.Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat. Genet. 2006; 38: 320-323Crossref PubMed Scopus (1163) Google Scholara Wnt homepage, http://wnt.stanford.edu. Open table in a new tab Wnt proteins are ∼40 kDa in size and contain many conserved cysteines (Tanaka et al., 2002Tanaka K. Kitagawa Y. Kadowaki T. Drosophila segment polarity gene product porcupine stimulates the posttranslational N-glycosylation of wingless in the endoplasmic reticulum.J. Biol. Chem. 2002; 277: 12816-12823Crossref PubMed Scopus (0) Google Scholar). Despite the initial discovery of Wnt nearly 30 years ago, efficient production and biochemical characterization of Wnt proteins remain challenging. The first successful purification of active mouse Wnt3A revealed that Wnts are lipid modified (Willert et al., 2003Willert K. Brown J.D. Danenberg E. Duncan A.W. Weissman I.L. Reya T. Yates III, J.R. Nusse R. Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature. 2003; 423: 448-452Crossref PubMed Scopus (0) Google Scholar). One of these is a mono-unsaturated fatty acid (palmitoleic acid) attached to a conserved serine (Takada et al., 2006Takada R. Satomi Y. Kurata T. Ueno N. Norioka S. Kondoh H. Takao T. Takada S. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion.Dev. Cell. 2006; 11: 791-801Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The lipids on Wnts are required for efficient signaling and may be important for Wnt secretion (Franch-Marro et al., 2008aFranch-Marro X. Wendler F. Griffith J. Maurice M.M. Vincent J.P. In vivo role of lipid adducts on Wingless.J. Cell Sci. 2008; 121: 1587-1592Crossref PubMed Scopus (48) Google Scholar, Kurayoshi et al., 2007Kurayoshi M. Yamamoto H. Izumi S. Kikuchi A. Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling.Biochem. J. 2007; 402: 515-523Crossref PubMed Scopus (0) Google Scholar, Willert et al., 2003Willert K. Brown J.D. Danenberg E. Duncan A.W. Weissman I.L. Reya T. Yates III, J.R. Nusse R. Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature. 2003; 423: 448-452Crossref PubMed Scopus (0) Google Scholar). Most recently, the structure of the Xenopus Wnt8 protein as bound to Frizzled was solved, revealing two domains on Wnt that interact with the receptor (Janda et al., 2012Janda C. Waghray D. Levin A. Thomas C. Garcia K. Structural basis of Wnt recognition by Frizzled.Science. 2012; (Published online May 31, 2012)Google Scholar). Interestingly, one of these domains contains the palmitoleic acid lipid, which projects into a pocket in the Frizzled CRD, a configuration that reinforces the importance of the lipid for signaling. The role of the lipid is also reflected by the requirement for Porcupine (Porc; Figure 1), a dedicated and highly conserved component of the Wnt pathway active only in Wnt-producing cells. Porc is a multipass transmembrane O-acyltransferase in the ER that is essential for Wnt palmitoylation and maturation (Hofmann, 2000Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling.Trends Biochem. Sci. 2000; 25: 111-112Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Kadowaki et al., 1996Kadowaki T. Wilder E. Klingensmith J. Zachary K. Perrimon N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.Genes Dev. 1996; 10: 3116-3128Crossref PubMed Google Scholar). Loss of Porcupine leads to retention of Wnt3A in the ER (Takada et al., 2006Takada R. Satomi Y. Kurata T. Ueno N. Norioka S. Kondoh H. Takao T. Takada S. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion.Dev. Cell. 2006; 11: 791-801Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) and a defect in Wg secretion in the Drosophila embryo (Kadowaki et al., 1996Kadowaki T. Wilder E. Klingensmith J. Zachary K. Perrimon N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.Genes Dev. 1996; 10: 3116-3128Crossref PubMed Google Scholar). The human gene (PORCN) is located on the X chromosome, and mutations lead to the rare genetic disorder focal dermal hypoplasia (Table 1). This disease is characterized by skin abnormalities and other developmental defects (Grzeschik et al., 2007Grzeschik K.H. Bornholdt D. Oeffner F. König A. del Carmen Boente M. Enders H. Fritz B. Hertl M. Grasshoff U. Höfling K. et al.Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia.Nat. Genet. 2007; 39: 833-835Crossref PubMed Scopus (163) Google Scholar, Wang et al., 2007Wang X. Reid Sutton V. Omar Peraza-Llanes J. Yu Z. Rosetta R. Kou Y.C. Eble T.N. Patel A. Thaller C. Fang P. Van den Veyver I.B. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia.Nat. Genet. 2007; 39: 836-838Crossref PubMed Scopus (151) Google Scholar). Mutations in the X-linked PORCN gene are lethal in males, consistent with the early embryonic lethality due to gastrulation defects observed in mouse knockouts (Barrott et al., 2011Barrott J.J. Cash G.M. Smith A.P. Barrow J.R. Murtaugh L.C. Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.Proc. Natl. Acad. Sci. USA. 2011; 108: 12752-12757Crossref PubMed Scopus (56) Google Scholar, Biechele et al., 2011Biechele S. Cox B.J. Rossant J. Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos.Dev. Biol. 2011; 355: 275-285Crossref PubMed Scopus (55) Google Scholar). Females survive with focal defects due to random X inactivation. The seven-transmembrane Wntless (Wls) protein provides an essential though less understood function in Wnt secretion (Bänziger et al., 2006Bänziger C. Soldini D. Schütt C. Zipperlen P. Hausmann G. Basler K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells.Cell. 2006; 125: 509-522Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Bartscherer et al., 2006Bartscherer K. Pelte N. Ingelfinger D. Boutros M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.Cell. 2006; 125: 523-533Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Goodman et al., 2006Goodman R.M. Thombre S. Firtina Z. Gray D. Betts D. Roebuck J. Spana E.P. Selva E.M. Sprinter: a novel transmembrane protein required for Wg secretion and signaling.Development. 2006; 133: 4901-4911Crossref PubMed Scopus (0) Google Scholar). Wls localizes to the Golgi network, endosomes, and the plasma membrane and binds Wnt proteins (Figure 1). In Wls mutant cells, Wg accumulates in the Golgi (Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Wingless secretion promotes and requires retromer-dependent cycling of Wntless.Nat. Cell Biol. 2008; 10: 178-185Crossref PubMed Scopus (144) Google Scholar). Wls is thought to act as a sorting receptor, taking Wnt from the Golgi to the plasma membrane. Intriguingly, there is evidence for Wls- and Wg-containing secreted vesicles in the Drosophila neuromuscular junction, where the Wg protein is tethered to the outside of the vesicles (Korkut et al., 2009Korkut C. Ataman B. Ramachandran P. Ashley J. Barria R. Gherbesi N. Budnik V. Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.Cell. 2009; 139: 393-404Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In this configuration, the Wg protein interacts with its receptor on the receiving muscle. Whether this mode of Wg transport and signaling operates in other contexts is presently unknown. Several studies in C. elegans have revealed that the retromer, an intracellular trafficking complex, is also required for Wnt signaling (Coudreuse et al., 2006Coudreuse D.Y. Roël G. Betist M.C. Destrée O. Korswagen H.C. Wnt gradient formation requires retromer function in Wnt-producing cells.Science. 2006; 312: 921-924Crossref PubMed Scopus (0) Google Scholar, Prasad and Clark, 2006Prasad B.C. Clark S.G. Wnt signaling establishes anteroposterior neuronal polarity and requires retromer in C. elegans.Development. 2006; 133: 1757-1766Crossref PubMed Scopus (0) Google Scholar). One of the key functions of the retromer complex involves the retrograde transport of specific endocytosed transmembrane proteins back to the trans-Golgi network. Current evidence indicates that the retromer retrieves endosomal Wls, which is otherwise destined to be degraded in lysosomes, trafficking it to the trans-Golgi network by retrograde transport (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network.Dev. Cell. 2008; 14: 120-131Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, Franch-Marro et al., 2008bFranch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M.M. Vincent J.P. Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex.Nat. Cell Biol. 2008; 10: 170-177Crossref PubMed Scopus (144) Google Scholar, Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Wingless secretion promotes and requires retromer-dependent cycling of Wntless.Nat. Cell Biol. 2008; 10: 178-185Crossref PubMed Scopus (144) Google Scholar, Yang et al., 2008Yang P.T. Lorenowicz M.J. Silhankova M. Coudreuse D.Y. Betist M.C. Korswagen H.C. Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells.Dev. Cell. 2008; 14: 140-147Abstract Full Text Full Text PDF PubMed Scopus (1