Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Function and biological roles of the Dickkopf family of Wnt modulators

Abstract

Dickkopf (Dkk) genes comprise an evolutionary conserved small gene family of four members (Dkk1-4) and a unique Dkk3-related gene, Dkkl1 (soggy). They encode secreted proteins that typically antagonize Wnt/β-catenin signaling, by inhibiting the Wnt coreceptors Lrp5 and 6. Additionally, Dkks are high affinity ligands for the transmembrane proteins Kremen1 and 2, which also modulate Wnt signaling. Dkks play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero–posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer's disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2

References

  • Abarzua F, Sakaguchi M, Takaishi M, Nasu Y, Kurose K, Ebara S et al. (2005). Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer Res 65: 9617–9622.

    Article  CAS  PubMed  Google Scholar 

  • Adamska M, MacDonald BT, Sarmast ZH, Oliver ER, Meisler MH . (2004). En1 and Wnt7a interact with Dkk1 during limb development in the mouse. Dev Biol 272: 134–144.

    Article  CAS  PubMed  Google Scholar 

  • Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J et al. (2006). Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25: 4116–4121.

    Article  CAS  PubMed  Google Scholar 

  • Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML . (2005). Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25: 4946–4955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andl T, Reddy ST, Gaddapara T, Millar SE . (2002). WNT signals are required for the initiation of hair follicle development. Dev Cell 2: 643–653.

    Article  CAS  PubMed  Google Scholar 

  • Aravind L, Koonin EV . (1998). A colipase fold in the carboxy-terminal domain of the Wnt antagonists – the Dickkopfs. Curr Biol 8: R477–R478.

    Article  CAS  PubMed  Google Scholar 

  • Aulehla A, Herrmann BG . (2004). Segmentation in vertebrates: clock and gradient finally joined. Genes Dev 18: 2060–2067.

    Article  CAS  PubMed  Google Scholar 

  • Aulehla A, Wehrle C, Brand-Saberi B, Kemler R, Gossler A, Kanzler B et al. (2003). Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev Cell 4: 395–406.

    Article  CAS  PubMed  Google Scholar 

  • Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi T et al. (2006). Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene 25: 2546–2557.

    Article  CAS  PubMed  Google Scholar 

  • Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML et al. (2003). High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18: 960–974.

    Article  CAS  PubMed  Google Scholar 

  • Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA . (2001). Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3: 683–686.

    Article  CAS  PubMed  Google Scholar 

  • Barrow JR, Thomas KR, Boussadia-Zahui O, Moore R, Kemler R, Capecchi MR et al. (2003). Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev 17: 394–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boisbouvier J, Albrand JP, Blackledge M, Jaquinod M, Schweitz H, Lazdunski M et al. (1998). A structural homologue of colipase in black mamba venom revealed by NMR floating disulphide bridge analysis. J Mol Biol 283: 205–219.

    Article  CAS  PubMed  Google Scholar 

  • Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA et al. (2002). High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346: 1513–1521.

    Article  CAS  PubMed  Google Scholar 

  • Brott BK, Sokol SY . (2002). Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Mol Cell Biol 22: 6100–6110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bullock CM, Li JD, Zhou QY . (2004). Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists. Mol Pharmacol 65: 582–588.

    Article  CAS  PubMed  Google Scholar 

  • Cadigan KM, Liu YI . (2006). Wnt signaling: complexity at the surface. J Cell Sci 119: 395–402.

    Article  CAS  PubMed  Google Scholar 

  • Cadigan KM, Nusse RM . (1997). Wnt signaling: a common theme in animal development. Genes Dev 11: 3286–3305.

    Article  CAS  PubMed  Google Scholar 

  • Cappuccio I, Calderone A, Busceti CL, Biagioni F, Pontarelli F, Bruno V et al. (2005). Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. J Neurosci 25: 2647–2657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A et al. (2004). Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci 24: 6021–6027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caricasole A, Ferraro T, Iacovelli L, Barletta E, Caruso A, Melchiorri D et al. (2003). Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 × LRP6 receptor complex and modulation by Dickkopf proteins. J Biol Chem 278: 37024–37031.

    Article  CAS  PubMed  Google Scholar 

  • Carter M, Chen X, Slowinska B, Minnerath S, Glickstein S, Shi L et al. (2005). Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Proc Natl Acad Sci USA 102: 12843–12848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chamorro MN, Schwartz DR, Vonica A, Brivanlou AH, Cho KR, Varmus HE . (2005). FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J 24: 73–84.

    Article  CAS  PubMed  Google Scholar 

  • Chapman SC, Brown R, Lees L, Schoenwolf GC, Lumsden A . (2004). Expression analysis of chick Wnt and frizzled genes and selected inhibitors in early chick patterning. Dev Dyn 229: 668–676.

    Article  CAS  PubMed  Google Scholar 

  • Church VL, Francis-West P . (2002). Wnt signalling during limb development. Int J Dev Biol 46: 927–936.

    CAS  PubMed  Google Scholar 

  • Davidson G, Mao B, Del Barco Barrantes I, Niehrs C . (2002). Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning. Development 129: 5587–5596.

    Article  CAS  PubMed  Google Scholar 

  • Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P et al. (2005). Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438: 867–872.

    Article  CAS  PubMed  Google Scholar 

  • De Robertis EM, Kuroda H . (2004). Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol 20: 285–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • del Barco Barrantes I, Davidson G, Gröne HJ, Westphal H, Niehrs C . (2003). Dkk1 and noggin cooperate in mammalian head induction. Genes Dev 17: 2239–2344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • del Barco Barrantes I, Montero-Pedrazuela A, Guadano-Ferraz A, Obregon MJ, Martinez de Mena R, Gailus-Durner V et al. (2006). Generation and characterization of dickkopf3 mutant mice. Mol Cell Biol 26: 2317–2326.

    Article  CAS  PubMed Central  Google Scholar 

  • Diep DB, Hoen N, Backman M, Machon O, Krauss S . (2004). Characterisation of the Wnt antagonists and their response to conditionally activated Wnt signalling in the developing mouse forebrain. Brain Res Dev Brain Res 153: 261–270.

    Article  CAS  PubMed  Google Scholar 

  • Esteve P, Bovolenta P . (2006). Secreted inducers in vertebrate eye development: more functions for old morphogens. Curr Opin Neurobiol 16: 13–19.

    Article  CAS  PubMed  Google Scholar 

  • Fedders H, Augustin R, Bosch TC . (2004). A Dickkopf-3-related gene is expressed in differentiating nematocytes in the basal metazoan Hydra. Dev Genes Evol 214: 72–80.

    Article  CAS  PubMed  Google Scholar 

  • Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP et al. (1999). Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J Biol Chem 274: 19465–19472.

    Article  CAS  PubMed  Google Scholar 

  • Fjeld K, Kettunen P, Furmanek T, Kvinnsland IH, Luukko K . (2005). Dynamic expression of Wnt signaling-related Dickkopf1, -2, and -3 mRNAs in the developing mouse tooth. Dev Dyn 233: 161–166.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Glinka A, Wu W, Onichtchouk D, Blumenstock C, Niehrs C . (1997). Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus. Nature 389: 517–519.

    Article  CAS  PubMed  Google Scholar 

  • Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM et al. (2001). LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107: 513–523.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Sancho JM, Aguilera O, Garcia JM, Pendas-Franco N, Pena C, Cal S et al. (2005). The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 24: 1098–1103.

    Article  CAS  PubMed  Google Scholar 

  • Greco TL, Takada S, Newhouse MM, McMahon JA, McMahon AP, Camper SA . (1996). Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev 10: 313–324.

    Article  CAS  PubMed  Google Scholar 

  • Gregory CA, Perry AS, Reyes E, Conley A, Gunn WG, Prockop DJ . (2005). Dkk-1-derived synthetic peptides and lithium chloride for the control and recovery of adult stem cells from bone marrow. J Biol Chem 280: 2309–2323.

    Article  CAS  PubMed  Google Scholar 

  • Grotewold L, Rüther U . (2002). The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death. EMBO J 21: 966–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grotewold L, Theil T, Rüther U . (1999). Expression pattern of dkk-1 during mouse limb development. Mech Dev 89: 151–153.

    Article  CAS  PubMed  Google Scholar 

  • Guder C, Pinho S, Nacak TG, Schmidt HA, Hobmayer B, Niehrs C et al. (2006). An ancient Wnt-Dickkopf antagonism in Hydra. Development 133: 901–911.

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto H, Itoh M, Yamanaka Y, Yamashita S, Shimizu T, Solnica-Krezel L et al. (2000). Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. Dev Biol 217: 138–152.

    Article  CAS  PubMed  Google Scholar 

  • He X, Semenov M, Tamai K, Zeng X . (2004). LDL receptor related proteins 5 and 6 in Wnt/beta catenin signaling: ARROWS point the way. Development 131: 1663–1677.

    Article  CAS  PubMed  Google Scholar 

  • Hino K, Satou Y, Yagi K, Satoh N . (2003). A genomewide survey of developmentally relevant genes in Ciona intestinalis. VI. Genes for Wnt, TGFbeta, Hedgehog and JAK/STAT signaling pathways. Dev Genes Evol 213: 264–272.

    Article  CAS  PubMed  Google Scholar 

  • Hoang BH, Kubo T, Healey JH, Yang R, Nathan SS, Kolb EA et al. (2004). Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res 64: 2734–2739.

    Article  CAS  PubMed  Google Scholar 

  • Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF et al. (2004). Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19: 2033–2040.

    Article  CAS  PubMed  Google Scholar 

  • Holmen SL, Robertson SA, Zylstra CR, Williams BO . (2005). Wnt-independent activation of beta-catenin mediated by a Dkk1-Fz5 fusion protein. Biochem Biophys Res Commun 328: 533–539.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh SY, Hsieh PS, Chiu CT, Chen WY . (2004). Dickkopf-3/REIC functions as a suppressor gene of tumor growth. Oncogene 23: 9183–9189.

    Article  CAS  PubMed  Google Scholar 

  • Idkowiak J, Weisheit G, Plitzner J, Viebahn C . (2004). Hypoblast controls mesoderm generation and axial patterning in the gastrulating rabbit embryo. Dev Genes Evol 214: 591–605.

    Article  PubMed  Google Scholar 

  • Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC et al. (2003). Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 130: 4295–4305.

    Article  CAS  PubMed  Google Scholar 

  • Kaneko KJ, DePamphilis ML . (2000). Soggy, a spermatocyte-specific gene, lies 3.8 kb upstream of and antipodal to TEAD-2, a transcription factor expressed at the beginning of mouse development. Nucleic Acids Res 28: 3982–3990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaser A, Winklmayr M, Lepperdinger G, Kreil G . (2003). The AVIT protein family. Secreted cysteine-rich vertebrate proteins with diverse functions. EMBO Rep 4: 469–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass II DA et al. (2002). Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157: 303–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawano Y, Kitaoka M, Hamada Y, Walker MM, Waxman J, Kypta RM . (2006). Regulation of prostate cell growth and morphogenesis by Dickkopf-3. Oncogene [E-pub ahead of print].

  • Kawano Y, Kypta R . (2003). Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116: 2627–2634.

    Article  CAS  PubMed  Google Scholar 

  • Kazanskaya O, Glinka A, Niehrs C . (2000). The role of Xenopus dickkopf1 in prechordal plate specification and neural patterning. Development 127: 4981–4992.

    CAS  PubMed  Google Scholar 

  • Kelly OG, Pinson KI, Skarnes WC . (2004). The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 131: 2803–2815.

    Article  CAS  PubMed  Google Scholar 

  • Kimura-Yoshida C, Nakano H, Okamura D, Nakao K, Yonemura S, Belo JA et al. (2005). Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm. Dev Cell 9: 639–650.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Ouchida M, Tsuji T, Hanafusa H, Miyazaki M, Namba M et al. (2002). Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. Gene 282: 151–158.

    Article  CAS  PubMed  Google Scholar 

  • Kohn AD, Moon RT . (2005). Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 38: 439–446.

    Article  CAS  PubMed  Google Scholar 

  • Kohn MJ, Kaneko KJ, DePamphilis ML . (2005). DkkL1 (Soggy), a Dickkopf family member, localizes to the acrosome during mammalian spermatogenesis. Mol Reprod Dev 71: 516–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kokubu C, Heinzmann U, Kokubu T, Sakai N, Kubota T, Kawai M et al. (2004). Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131: 5469–5480.

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Bryant HU, Macdougald OA . (2006). Regulation of bone mass by Wnt signaling. J Clin Invest 116: 1202–1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L et al. (1999). Functional and structural diversity of the human Dickkopf gene family. Gene 238: 301–313.

    Article  CAS  PubMed  Google Scholar 

  • Kurose K, Sakaguchi M, Nasu Y, Ebara S, Kaku H, Kariyama R et al. (2004). Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma. J Urol 171: 1314–1318.

    Article  CAS  PubMed  Google Scholar 

  • Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N et al. (2004). Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma. Biochem Biophys Res Commun 323: 1246–1250.

    Article  CAS  PubMed  Google Scholar 

  • Leonard DM, Stachelek SJ, Safran M, Farwell AP, Kowalik TF, Leonard JL . (2000). Cloning, expression, and functional characterization of the substrate binding subunit of rat type II iodothyronine 5'-deiodinase. J Biol Chem 275: 25194–25201.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M et al. (2006). Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39: 754–766.

    Article  CAS  PubMed  Google Scholar 

  • Li L, Mao J, Sun L, Liu W, Wu D . (2002). Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem 277: 5977–5981.

    Article  CAS  PubMed  Google Scholar 

  • Li X, Liu P, Liu W, Maye P, Zhang J, Zhang Y et al. (2005). Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37: 945–952.

    Article  CAS  PubMed  Google Scholar 

  • Liu G, Bafico A, Aaronson SA . (2005). The mechanism of endogenous receptor activation functionally distinguishes prototype canonical and noncanonical Wnts. Mol Cell Biol 25: 3475–3482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lodygin D, Epanchintsev A, Menssen A, Diebold J, Hermeking H . (2005). Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res 65: 4218–4227.

    Article  CAS  PubMed  Google Scholar 

  • Lovicu FJ, McAvoy JW . (2005). Growth factor regulation of lens development. Dev Biol 280: 1–14.

    Article  CAS  PubMed  Google Scholar 

  • Luke GN, Castro LF, McLay K, Bird C, Coulson A, Holland PW . (2003). Dispersal of NK homeobox gene clusters in amphioxus and humans. Proc Natl Acad Sci USA 100: 5292–5295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald BT, Adamska M, Meisler MH . (2004). Hypomorphic expression of Dkk1 in the doubleridge mouse: dose dependence and compensatory interactions with Lrp6. Development 131: 2543–2552.

    Article  CAS  PubMed  Google Scholar 

  • Mao B, Niehrs C . (2003). Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene 302: 179–183.

    Article  CAS  PubMed  Google Scholar 

  • Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler B et al. (2002). Kremens are novel Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417: 664–667.

    Article  CAS  PubMed  Google Scholar 

  • Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A et al. (2001a). LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321–325.

    Article  CAS  PubMed  Google Scholar 

  • Mao J, Wang J, Liu B, Pan W, Farr III GH, Flynn C et al. (2001b). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7: 801–809.

    Article  CAS  PubMed  Google Scholar 

  • Marvin MJ, Di Rocco G, Gardiner A, Bush SM, Lassar AB . (2001). Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev 15: 316–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mikels AJ, Nusse R . (2006). Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4: e115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mikheev AM, Mikheeva SA, Liu B, Cohen P, Zarbl H . (2004). A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation. Carcinogenesis 25: 47–59.

    Article  CAS  PubMed  Google Scholar 

  • Monaghan AP, Kioschis P, Wu W, Zuniga A, Bock D, Poustka A et al. (1999). Dickkopf genes are co-ordinately expressed in mesodermal lineages. Mech Dev 87: 45–56.

    Article  CAS  PubMed  Google Scholar 

  • Montero-Pedrazuela A, Bernal J, Guadano-Ferraz A . (2003). Divergent expression of type 2 deiodinase and the putative thyroxine-binding protein p29, in rat brain, suggests that they are functionally unrelated proteins. Endocrinology 144: 1045–1052.

    Article  CAS  PubMed  Google Scholar 

  • Moon RT, Kohn AD, De Ferrari GV, Kaykas A . (2004). WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5: 691–701.

    Article  CAS  PubMed  Google Scholar 

  • Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B et al. (2006). Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21: 934–945.

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay M, Gorivodsky M, Shtrom S, Grinberg A, Niehrs C, Morasso MI et al. (2006). Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium. Development 133: 2149–2154.

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L et al. (2001). Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1: 423–434.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Aoki S, Kitajima K, Takahashi T, Matsumoto K . (2001). Molecular cloning and characterization of Kremen, a novel kringle- containing transmembrane protein. Biochim Biophys Acta 1518: 63–72.

    Article  CAS  PubMed  Google Scholar 

  • Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M et al. (2003). Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33: 416–421.

    Article  CAS  PubMed  Google Scholar 

  • Nie X . (2005). Dkk1, -2, and -3 expression in mouse craniofacial development. J Mol Histol 36: 367–372.

    Article  CAS  PubMed  Google Scholar 

  • Nie X, Luukko K, Fjeld K, Kvinnsland IH, Kettunen P . (2005). Developmental expression of Dkk1-3 and Mmp9 and apoptosis in cranial base of mice. J Mol Histol 36: 419–426.

    Article  CAS  PubMed  Google Scholar 

  • Niehrs C . (2004a). Norrin and frizzled; a new vein for the eye. Dev Cell 6: 453–454.

    Article  CAS  PubMed  Google Scholar 

  • Niehrs C . (2004b). Regionally specific induction by the Spemann-Mangold organizer. Nat Rev Genet 5: 425–434.

    Article  CAS  PubMed  Google Scholar 

  • Nozaki I, Tsuji T, Iijima O, Ohmura Y, Andou A, Miyazaki M et al. (2001). Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer. Int J Oncol 19: 117–121.

    CAS  PubMed  Google Scholar 

  • Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B et al. (2003). The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8: 645–654.

    Article  CAS  PubMed  Google Scholar 

  • Orme MH, Giannini AL, Vivanco MD, Kypta RM . (2003). Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells. Mol Cell Neurosci 24: 673–686.

    Article  CAS  PubMed  Google Scholar 

  • Pandur P, Lasche M, Eisenberg LM, Kuhl M . (2002). Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418: 636–641.

    Article  CAS  PubMed  Google Scholar 

  • Patil MA, Chua MS, Pan KH, Lin R, Lih CJ, Cheung ST et al. (2005). An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma. Oncogene 24: 3737–3747.

    Article  CAS  PubMed  Google Scholar 

  • Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC . (2000). An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407: 535–538.

    Article  CAS  PubMed  Google Scholar 

  • Polakis P . (2000). Wnt signaling and cancer. Genes Dev 14: 1837–1851.

    CAS  PubMed  Google Scholar 

  • Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Dimopoulos MA et al. (2006). Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 119: 1728–1731.

    Article  CAS  PubMed  Google Scholar 

  • Pollard SL, Holland PW . (2000). Evidence for 14 homeobox gene clusters in human genome ancestry. Curr Biol 10: 1059–1062.

    Article  CAS  PubMed  Google Scholar 

  • Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Barrios M et al. (2004). Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia. Br J Cancer 91: 707–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider VA, Mercola M . (2001). Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev 15: 304–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X . (2001). Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 11: 951–961.

    Article  CAS  PubMed  Google Scholar 

  • Shinya M, Eschbach C, Clark M, Lehrach H, Furutani-Seiki M . (2000). Zebrafish Dkk1, induced by the pre-MBT Wnt signaling, is secreted from the prechordal plate and patterns the anterior neural plate. Mech Dev 98: 3–17.

    Article  CAS  PubMed  Google Scholar 

  • Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS . (2002). Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene 21: 878–889.

    Article  CAS  PubMed  Google Scholar 

  • Soshnikova N, Zechner D, Huelsken J, Mishina Y, Behringer RR, Taketo MM et al. (2003). Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev 17: 1963–1968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szeto TH, Wang XH, Smith R, Connor M, Christie MJ, Nicholson GM et al. (2000). Isolation of a funnel-web spider polypeptide with homology to mamba intestinal toxin 1 and the embryonic head inducer Dickkopf-1. Toxicon 38: 429–442.

    Article  CAS  PubMed  Google Scholar 

  • Tada M, Concha ML, Heisenberg CP . (2002). Non-canonical Wnt signalling and regulation of gastrulation movements. Semin Cell Dev Biol 13: 251–260.

    Article  CAS  PubMed  Google Scholar 

  • Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. (2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349: 2483–2494.

    Article  CAS  PubMed  Google Scholar 

  • Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M . (2000). A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem Biophys Res Commun 268: 20–24.

    Article  CAS  PubMed  Google Scholar 

  • van der Horst G, van der Werf SM, Farih-Sips H, van Bezooijen RL, Lowik CW, Karperien M . (2005). Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res 20: 1867–1877.

    Article  CAS  PubMed  Google Scholar 

  • Van Raay TJ, Vetter ML . (2004). Wnt/frizzled signaling during vertebrate retinal development. Dev Neurosci 26: 352–358.

    Article  CAS  PubMed  Google Scholar 

  • van Tilbeurgh H, Bezzine S, Cambillau C, Verger R, Carriere F . (1999). Colipase: structure and interaction with pancreatic lipase. Biochim Biophys Acta 1441: 173–184.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Shou J, Chen X . (2000). Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Oncogene 19: 1843–1848.

    Article  CAS  PubMed  Google Scholar 

  • Wirths O, Waha A, Weggen S, Schirmacher P, Kuhne T, Goodyer CG et al. (2003). Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors. Lab Invest 83: 429–434.

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Glinka A, Delius H, Niehrs C . (2000). Mutual antagonism between dickkopf1 and -2 regulates Wnt/beta-catenin signalling. Curr Biol 10: 1611–1614.

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi Y, Itami S, Watabe H, Yasumoto K, Abdel-Malek ZA, Kubo T et al. (2004). Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation. J Cell Biol 165: 275–285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshikawa S, McKinnon RD, Kokel M, Thomas JB . (2003). Wnt-mediated axon guidance via the Drosophila derailed receptor. Nature 422: 583–588.

    Article  CAS  PubMed  Google Scholar 

  • Zakin L, Reversade B, Virlon B, Rusniok C, Glaser P, Elalouf JM et al. (2000). Gene expression profiles in normal and Otx2−/− early gastrulating mouse embryos. Proc Natl Acad Sci USA 97: 14388–14393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R et al. (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438: 873–877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank Kristina Ellwanger, Andrei Glinka and Sonia Pinho for critically reading the manuscript and B Engelhardt for artwork. This work was supported by the Deutsche Forschungsgemeinschaft (Ni 286/12-1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Niehrs.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Niehrs, C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 25, 7469–7481 (2006). https://doi.org/10.1038/sj.onc.1210054

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210054

Keywords

  • Dkk
  • Wnt
  • Kremen
  • embryo
  • Lrp6
  • colipase fold

This article is cited by

Search

Quick links