Cellular and Molecular Life Sciences

, Volume 71, Issue 18, pp 3553–3567 | Cite as

Wnt–Notch signalling crosstalk in development and disease

  • Giovanna M. Collu
  • Ana Hidalgo-Sastre
  • Keith BrennanEmail author


The Notch and Wnt pathways are two of only a handful of highly conserved signalling pathways that control cell-fate decisions during animal development (Pires-daSilva and Sommer in Nat Rev Genet 4: 39–49, 2003). These two pathways are required together to regulate many aspects of metazoan development, ranging from germ layer patterning in sea urchins (Peter and Davidson in Nature 474: 635–639, 2011) to the formation and patterning of the fly wing (Axelrod et al in Science 271:1826–1832, 1996; Micchelli et al in Development 124:1485–1495, 1997; Rulifson et al in Nature 384:72–74, 1996), the spacing of the ciliated cells in the epidermis of frog embryos (Collu et al in Development 139:4405–4415, 2012) and the maintenance and turnover of the skin, gut lining and mammary gland in mammals (Clayton et al in Nature 446:185–189, 2007; Clevers in Cell 154:274–284, 2013; Doupe et al in Dev Cell 18:317–323, 2010; Lim et al in Science 342:1226–1230, 2013; Lowell et al in Curr Biol 10:491–500, 2000; van et al in Nature 435:959–963, 2005; Yin et al in Nat Methods 11:106–112, 2013). In addition, many diseases, including several cancers, are caused by aberrant signalling through the two pathways (Bolós et al in Endocr Rev 28: 339–363, 2007; Clevers in Cell 127: 469–480, 2006). In this review, we will outline the two signalling pathways, describe the different points of interaction between them, and cover how these interactions influence development and disease.


Notch Wnt Signalling crosstalk Development Disease 


  1. 1.
    Pires-daSilva A, Sommer RJ (2003) The evolution of signalling pathways in animal development. Nat Rev Genet 4:39–49PubMedGoogle Scholar
  2. 2.
    Peter IS, Davidson EH (2011) A gene regulatory network controlling the embryonic specification of endoderm. Nature 474:635–639PubMedCentralPubMedGoogle Scholar
  3. 3.
    Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N (1996) Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science 271:1826–1832PubMedGoogle Scholar
  4. 4.
    Micchelli CA, Rulifson EJ, Blair SS (1997) The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development 124:1485–1495PubMedGoogle Scholar
  5. 5.
    Rulifson EJ, Micchelli CA, Axelrod JD, Perrimon N, Blair SS (1996) Wingless refines its own expression domain on the Drosophila wing margin. Nature 384:72–74PubMedGoogle Scholar
  6. 6.
    Collu GM, Hidalgo-Sastre A, Acar A, Bayston L, Gildea C, Leverentz MK, Mills CG, Owens TW, Meurette O, Dorey K, Brennan K (2012) Dishevelled limits Notch signalling through inhibition of CSL. Development 139:4405–4415PubMedCentralPubMedGoogle Scholar
  7. 7.
    Clayton E, Doupe DP, Klein AM, Winton DJ, Simons BD, Jones PH (2007) A single type of progenitor cell maintains normal epidermis. Nature 446:185–189PubMedGoogle Scholar
  8. 8.
    Clevers H (2013) The intestinal crypt, a prototype stem cell compartment. Cell 154:274–284PubMedGoogle Scholar
  9. 9.
    Doupe DP, Klein AM, Simons BD, Jones PH (2010) The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev Cell 18:317–323PubMedGoogle Scholar
  10. 10.
    Lim X, Tan SH, Koh WL, Chau RM, Yan KS, Kuo CJ, van Amerongen R, Klein AM, Nusse R (2013) Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342:1226–1230PubMedCentralPubMedGoogle Scholar
  11. 11.
    Lowell S, Jones P, Le Roux I, Dunne J, Watt FM (2000) Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol 10:491–500PubMedGoogle Scholar
  12. 12.
    van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedGoogle Scholar
  13. 13.
    Yin X, Farin HF, van Es JH, Clevers H, Langer R, Karp JM (2013) Niche-independent high-purity cultures of Lgr5 intestinal stem cells and their progeny. Nat Methods 11:106–112PubMedGoogle Scholar
  14. 14.
    Bolós V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363PubMedGoogle Scholar
  15. 15.
    Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480PubMedGoogle Scholar
  16. 16.
    Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC (2004) Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 24:9265–9273PubMedCentralPubMedGoogle Scholar
  17. 17.
    Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T (1995) Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol 5:1416–1423PubMedGoogle Scholar
  18. 18.
    Ehebauer MT, Chirgadze DY, Hayward P, Martinez Arias A, Blundell TL (2005) High-resolution crystal structure of the human Notch 1 ankyrin domain. Biochem J 392:13–20PubMedCentralPubMedGoogle Scholar
  19. 19.
    Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (1991) Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 67:687–699PubMedGoogle Scholar
  20. 20.
    Nichols JT, Miyamoto A, Olsen SL, D’Souza B, Yao C, Weinmaster G (2007) DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176:445–458PubMedCentralPubMedGoogle Scholar
  21. 21.
    Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194:237–255PubMedGoogle Scholar
  22. 22.
    Fischer A, Gessler M (2007) Delta-Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35:4583–4596PubMedCentralPubMedGoogle Scholar
  23. 23.
    Jeffries S, Robbins DJ, Capobianco AJ (2002) Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line. Mol Cell Biol 22:3927–3941PubMedCentralPubMedGoogle Scholar
  24. 24.
    Joshi I, Minter LM, Telfer J, Demarest RM, Capobianco AJ, Aster JC, Sicinski P, Fauq A, Golde TE, Osborne BA (2009) Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 113:1689–1698PubMedCentralPubMedGoogle Scholar
  25. 25.
    Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S, Efstratiadis A (2006) Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA 103:9262–9267PubMedCentralPubMedGoogle Scholar
  26. 26.
    Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O’Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA (2006) Notch1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103:18261–18266PubMedCentralPubMedGoogle Scholar
  27. 27.
    Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436PubMedCentralPubMedGoogle Scholar
  28. 28.
    Ronchini C, Capobianco AJ (2001) Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol 21:5925–5934PubMedCentralPubMedGoogle Scholar
  29. 29.
    Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–2109PubMedCentralPubMedGoogle Scholar
  30. 30.
    Kovall RA, Blacklow SC (2010) Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol 92:31–71PubMedGoogle Scholar
  31. 31.
    Hurlbut GD, Kankel MW, Lake RJ, Artavanis-Tsakonas S (2007) Crossing paths with Notch in the hyper-network. Curr Opin Cell Biol 19:166–175PubMedGoogle Scholar
  32. 32.
    Blokzijl A, Dahlqvist C, Reissmann E, Falk A, Moliner A, Lendahl U, Ibanez CF (2003) Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol 163:723–728PubMedCentralPubMedGoogle Scholar
  33. 33.
    Dahlqvist C, Blokzijl A, Chapman G, Falk A, Dannaeus K, Ibanez CF, Lendahl U (2003) Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation. Development 130:6089–6099PubMedGoogle Scholar
  34. 34.
    Ross DA, Kadesch T (2001) The notch intracellular domain can function as a coactivator for LEF-1. Mol Cell Biol 21:7537–7544PubMedCentralPubMedGoogle Scholar
  35. 35.
    Wang J, Shelly L, Miele L, Boykins R, Norcross MA, Guan E (2001) Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain. J Immunol 167:289–295PubMedGoogle Scholar
  36. 36.
    McGill MA, Dho SE, Weinmaster G, McGlade CJ (2009) Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem 284:26427–26438PubMedCentralPubMedGoogle Scholar
  37. 37.
    Jehn BM, Dittert I, Beyer S, von der Mark K, Bielke W (2002) c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. J Biol Chem 277:8033–8040PubMedGoogle Scholar
  38. 38.
    Pasternak SH, Bagshaw RD, Guiral M, Zhang S, Ackerley CA, Pak BJ, Callahan JW, Mahuran DJ (2003) Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. J Biol Chem 278:26687–26694PubMedGoogle Scholar
  39. 39.
    Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A (1998) Axin, a negative regulator of the Wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem 273:10823–10826PubMedGoogle Scholar
  40. 40.
    Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998) Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 8:573–581PubMedGoogle Scholar
  41. 41.
    Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT (1996) The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10:1443–1454PubMedGoogle Scholar
  42. 42.
    Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I (2002) Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 16:1066–1076PubMedCentralPubMedGoogle Scholar
  43. 43.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847PubMedGoogle Scholar
  44. 44.
    Yanagawa S, Matsuda Y, Lee JS, Matsubayashi H, Sese S, Kadowaki T, Ishimoto A (2002) Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. EMBO J 21:1733–1742PubMedCentralPubMedGoogle Scholar
  45. 45.
    Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16:3797–3804PubMedCentralPubMedGoogle Scholar
  46. 46.
    Latres E, Chiaur DS, Pagano M (1999) The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 18:849–854PubMedGoogle Scholar
  47. 47.
    Peifer M, McCrea PD, Green KJ, Wieschaus E, Gumbiner BM (1992) The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol 118:681–691PubMedGoogle Scholar
  48. 48.
    Heuberger J, Birchmeier W (2010) Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol 2:a002915PubMedCentralPubMedGoogle Scholar
  49. 49.
    Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D (1997) A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev 11:2359–2370PubMedCentralPubMedGoogle Scholar
  50. 50.
    Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H, Peifer M, Bejsovec A (1998) Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395:604–608PubMedGoogle Scholar
  51. 51.
    van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136:3205–3214PubMedGoogle Scholar
  52. 52.
    Tolwinski NS, Wieschaus E (2004) Rethinking WNT signaling. Trends Genet 20:177–181PubMedGoogle Scholar
  53. 53.
    Tolwinski NS, Wieschaus E (2004) A nuclear function for armadillo/beta-catenin. PLoS Biol 2:E95PubMedCentralPubMedGoogle Scholar
  54. 54.
    Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86:391–399PubMedGoogle Scholar
  55. 55.
    van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H (1997) Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88:789–799PubMedGoogle Scholar
  56. 56.
    Daniels DL, Weis WI (2005) Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol 12:364–371PubMedGoogle Scholar
  57. 57.
    Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Zullig S, Basler K (2002) Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 109:47–60PubMedGoogle Scholar
  58. 58.
    Parker DS, Jemison J, Cadigan KM (2002) Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development 129:2565–2576PubMedGoogle Scholar
  59. 59.
    Thompson B, Townsley F, Rosin-Arbesfeld R, Musisi H, Bienz M (2002) A new nuclear component of the Wnt signalling pathway. Nat Cell Biol 4:367–373PubMedGoogle Scholar
  60. 60.
    Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22:1172–1183PubMedCentralPubMedGoogle Scholar
  61. 61.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512PubMedGoogle Scholar
  62. 62.
    Adler PN (1992) The genetic control of tissue polarity in Drosophila. BioEssays 14:735–741PubMedGoogle Scholar
  63. 63.
    Vinson CR, Adler PN (1987) Directional non-cell autonomy and the transmission of polarity information by the frizzled gene of Drosophila. Nature 329:549–551PubMedGoogle Scholar
  64. 64.
    Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT (2000) The Wnt/Ca2+pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 16:279–283PubMedGoogle Scholar
  65. 65.
    Klein T, Arias AM (1999) The vestigial gene product provides a molecular context for the interpretation of signals during the development of the wing in Drosophila. Development 126:913–925PubMedGoogle Scholar
  66. 66.
    Jin YH, Kim H, Ki H, Yang I, Yang N, Lee KY, Kim N, Park HS, Kim K (2009) Beta-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochim Biophys Acta 1793:290–299PubMedGoogle Scholar
  67. 67.
    Yamamizu K, Matsunaga T, Uosaki H, Fukushima H, Katayama S, Hiraoka-Kanie M, Mitani K, Yamashita JK (2010) Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors. J Cell Biol 189:325–338PubMedCentralPubMedGoogle Scholar
  68. 68.
    Galceran J, Sustmann C, Hsu SC, Folberth S, Grosschedl R (2004) LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis. Genes Dev 18:2718–2723PubMedCentralPubMedGoogle Scholar
  69. 69.
    Dequeant ML, Glynn E, Gaudenz K, Wahl M, Chen J, Mushegian A, Pourquie O (2006) A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314:1595–1598PubMedGoogle Scholar
  70. 70.
    Amoyel M, Cheng YC, Jiang YJ, Wilkinson DG (2005) Wnt1 regulates neurogenesis and mediates lateral inhibition of boundary cell specification in the zebrafish hindbrain. Development 132:775–785PubMedGoogle Scholar
  71. 71.
    Cheng YC, Amoyel M, Qiu X, Jiang YJ, Xu Q, Wilkinson DG (2004) Notch activation regulates the segregation and differentiation of rhombomere boundary cells in the zebrafish hindbrain. Dev Cell 6:539–550PubMedGoogle Scholar
  72. 72.
    de Celis JF, Garcia-Bellido A, Bray SJ (1996) Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development 122:359–369PubMedGoogle Scholar
  73. 73.
    Micchelli CA, Blair SS (1999) Dorsoventral lineage restriction in wing imaginal discs requires Notch. Nature 401:473–476PubMedGoogle Scholar
  74. 74.
    Rulifson EJ, Blair SS (1995) Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila. Development 121:2813–2824PubMedGoogle Scholar
  75. 75.
    Klein T, Arias AM (1998) Different spatial and temporal interactions between Notch, wingless, and vestigial specify proximal and distal pattern elements of the wing in Drosophila. Dev Biol 194:196–212PubMedGoogle Scholar
  76. 76.
    Jayasena CS, Ohyama T, Segil N, Groves AK (2008) Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 135:2251–2261PubMedCentralPubMedGoogle Scholar
  77. 77.
    Zhou J, Cheng P, Youn JI, Cotter MJ, Gabrilovich DI (2009) Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity 30:845–859PubMedCentralPubMedGoogle Scholar
  78. 78.
    del Alamo D, Mlodzik M (2006) Frizzled/PCP-dependent asymmetric neuralized expression determines R3/R4 fates in the Drosophila eye. Dev Cell 11:887–894PubMedGoogle Scholar
  79. 79.
    Gu B, Watanabe K, Sun P, Fallahi M, Dai X (2013) Chromatin effector Pygo2 mediates Wnt–notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells. Cell Stem Cell 13:48–61PubMedCentralPubMedGoogle Scholar
  80. 80.
    Hayward P, Brennan K, Sanders P, Balayo T, DasGupta R, Perrimon N, Martinez-Arias A (2005) Notch modulates Wnt signalling by associating with Armadillo/β-catenin and regulating its transcriptional activity. Development 132:1819–1830PubMedCentralPubMedGoogle Scholar
  81. 81.
    Munoz-Descalzo S, Sanders PG, Montagne C, Johnson RI, Balayo T, Arias AM (2010) Wingless modulates the ligand independent traffic of Notch through Dishevelled. Fly (Austin) 4:182–193Google Scholar
  82. 82.
    Ramain P, Khechumian K, Seugnet L, Arbogast N, Ackermann C, Heitzler P (2001) Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate. Current Biol 11:1729–1738Google Scholar
  83. 83.
    Brennan K, Klein T, Wilder E, Arias AM (1999) Wingless modulates the effects of dominant negative notch molecules in the developing wing of Drosophila. Dev Biol 216:210–229PubMedGoogle Scholar
  84. 84.
    Capilla A, Johnson R, Daniels M, Benavente M, Bray SJ, Galindo MI (2012) Planar cell polarity controls directional Notch signaling in the Drosophila leg. Development 139:2584–2593PubMedCentralPubMedGoogle Scholar
  85. 85.
    Strutt D, Johnson R, Cooper K, Bray S (2002) Asymmetric localization of frizzled and the determination of notch-dependent cell fate in the Drosophila eye. Curr Biol 12:813–824PubMedGoogle Scholar
  86. 86.
    Deblandre GA, Wettstein DA, Koyano-Nakagawa N, Kintner C (1999) A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos. Development 126:4715–4728PubMedGoogle Scholar
  87. 87.
    Foltz DR, Santiago MC, Berechid BE, Nye JS (2002) Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12:1006–1011PubMedGoogle Scholar
  88. 88.
    Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A (2003) Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 278:32227–32235PubMedGoogle Scholar
  89. 89.
    Brennan K, Tateson R, Lewis K, Arias AM (1997) A functional analysis of Notch mutations in Drosophila. Genetics 147:177–188PubMedCentralPubMedGoogle Scholar
  90. 90.
    Couso JP, Martinez Arias A (1994) Notch is required for wingless signaling in the epidermis of Drosophila. Cell 79:259–272PubMedGoogle Scholar
  91. 91.
    Lawrence N, Langdon T, Brennan K, Arias AM (2001) Notch signaling targets the Wingless responsiveness of a Ubx visceral mesoderm enhancer in Drosophila. Current Biol 11:375–385Google Scholar
  92. 92.
    Wesley CS (1999) Notch and wingless regulate expression of cuticle patterning genes. Mol Cell Biol 19:5743–5758PubMedCentralPubMedGoogle Scholar
  93. 93.
    Young MW, Wesley CS (1997) Diverse roles for the Notch receptor in the development of D. melanogaster. Perspect Dev Neurobiol 4:345–355PubMedGoogle Scholar
  94. 94.
    Sanders PG, Munoz-Descalzo S, Balayo T, Wirtz-Peitz F, Hayward P, Arias AM (2009) Ligand-independent traffic of Notch buffers activated Armadillo in Drosophila. PLoS Biol 7:e1000169PubMedCentralPubMedGoogle Scholar
  95. 95.
    Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V, Srivastava D (2011) Notch post-translationally regulates beta-catenin protein in stem and progenitor cells. Nat Cell Biol 13:1244–1251PubMedCentralPubMedGoogle Scholar
  96. 96.
    Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11:951–957PubMedCentralPubMedGoogle Scholar
  97. 97.
    Yeh JT, Binari R, Gocha T, Dasgupta R, Perrimon N (2013) PAPTi: a peptide aptamer interference toolkit for perturbation of protein-protein interaction networks. Sci Rep 3:1156PubMedCentralPubMedGoogle Scholar
  98. 98.
    Acosta H, Lopez SL, Revinski DR, Carrasco AE (2011) Notch destabilises maternal beta-catenin and restricts dorsal-anterior development in Xenopus. Development 138:2567–2579PubMedGoogle Scholar
  99. 99.
    Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E (2006) Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem 281:6203–6210PubMedGoogle Scholar
  100. 100.
    Kim HA, Koo BK, Cho JH, Kim YY, Seong J, Chang HJ, Oh YM, Stange DE, Park JG, Hwang D, Kong YY (2012) Notch1 counteracts WNT/beta-catenin signaling through chromatin modification in colorectal cancer. J Clin Invest 122:3248–3259PubMedCentralPubMedGoogle Scholar
  101. 101.
    Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T (2008) Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol 28:7427–7441PubMedCentralPubMedGoogle Scholar
  102. 102.
    Hayward P, Kalmar T, Arias AM (2008) Wnt/Notch signalling and information processing during development. Development 135:411–424PubMedGoogle Scholar
  103. 103.
    Brack AS, Conboy IM, Conboy MJ, Shen J, Rando TA (2008) A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell Stem Cell 2:50–59PubMedGoogle Scholar
  104. 104.
    Rios AC, Serralbo O, Salgado D, Marcelle C (2011) Neural crest regulates myogenesis through the transient activation of NOTCH. Nature 473:532–535PubMedGoogle Scholar
  105. 105.
    Riley BB, Chiang MY, Storch EM, Heck R, Buckles GR, Lekven AC (2004) Rhombomere boundaries are Wnt signaling centres that regulate metameric patterning in the zebrafish hindbrain. Dev Dyn 231:278–291PubMedGoogle Scholar
  106. 106.
    Buceta J, Herranz H, Canela-Xandri O, Reigada R, Sagues F, Milan M (2007) Robustness and stability of the gene regulatory network involved in DV boundary formation in the Drosophila wing. PLoS One 2:e602PubMedCentralPubMedGoogle Scholar
  107. 107.
    Li A, Chen M, Jiang TX, Wu P, Nie Q, Widelitz R, Chuong CM (2013) Shaping organs by a wingless-int/Notch/nonmuscle myosin module which orients feather bud elongation. Proc Natl Acad Sci USA 110:E1452–E1461PubMedCentralPubMedGoogle Scholar
  108. 108.
    Martinez-Arias A, Hayward P (2006) Filtering transcriptional noise during development: concepts and mechanisms. Nat Rev Genet 7:34–44Google Scholar
  109. 109.
    Baylies MK, Martinez Arias A, Bate M (1995) Wingless is required for the formation of a subset of muscle founder cells during Drosophila embryogenesis. Development 121:3829–3837PubMedGoogle Scholar
  110. 110.
    Cubas P, de Celis JF, Campuzano S, Modolell J (1991) Proneural clusters of achaete-scute expression and the generation of sensory organs in the Drosophila imaginal wing disc. Genes Dev 5:996–1008PubMedGoogle Scholar
  111. 111.
    Heitzler P, Simpson P (1991) The choice of cell fate in the epidermis of Drosophila. Cell 64:1083–1092PubMedGoogle Scholar
  112. 112.
    Parks AL, Muskavitch MA (1993) Delta function is required for bristle organ determination and morphogenesis in Drosophila. Dev Biol 157:484–496PubMedGoogle Scholar
  113. 113.
    Skeath JB, Carroll SB (1991) Regulation of achaete-scute gene expression and sensory organ pattern formation in the Drosophila wing. Genes Dev 5:984–995PubMedGoogle Scholar
  114. 114.
    Bernard F, Krejci A, Housden B, Adryan B, Bray SJ (2010) Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors. Development 137:2633–2642PubMedCentralPubMedGoogle Scholar
  115. 115.
    Terriente-Felix A, Li J, Collins S, Mulligan A, Reekie I, Bernard F, Krejci A, Bray S (2013) Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme. Development 140:926–937PubMedCentralPubMedGoogle Scholar
  116. 116.
    de Navascues J, Perdigoto CN, Bian Y, Schneider MH, Bardin AJ, Martinez-Arias A, Simons BD (2012) Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J 31:2473–2485PubMedCentralPubMedGoogle Scholar
  117. 117.
    Lin G, Xu N, Xi R (2008) Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 455:1119–1123PubMedGoogle Scholar
  118. 118.
    Ohlstein B, Spradling A (2007) Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315:988–992PubMedGoogle Scholar
  119. 119.
    Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850PubMedGoogle Scholar
  120. 120.
    van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, Thiele A, van den Born M, Begthel H, Brabletz T, Taketo MM, Clevers H (2005) Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7:381–386PubMedGoogle Scholar
  121. 121.
    van Es JH, Sato T, van de Wetering M, Lyubimova A, Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H (2012) Dll1 + secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14:1099–1104PubMedCentralPubMedGoogle Scholar
  122. 122.
    Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernandez-Majada V, Grilli A, Lopez-Bigas N, Bellora N, Alba MM, Torres F, Dunach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A, Espinosa L (2009) Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA 106:6315–6320PubMedCentralPubMedGoogle Scholar
  123. 123.
    Lopez-Garcia C, Klein AM, Simons BD, Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330:822–825PubMedGoogle Scholar
  124. 124.
    Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143:134–144PubMedGoogle Scholar
  125. 125.
    Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat ML, Oakes SR, Lindeman GJ, Visvader JE (2008) Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3:429–441PubMedGoogle Scholar
  126. 126.
    van Amerongen R, Bowman AN, Nusse R (2012) Developmental stage and time dictate the fate of Wnt/beta-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11:387–400PubMedGoogle Scholar
  127. 127.
    Yalcin-Ozuysal O, Fiche M, Guitierrez M, Wagner KU, Raffoul W, Brisken C (2010) Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates. Cell Death Differ 17:1600–1612PubMedGoogle Scholar
  128. 128.
    Zeng YA, Nusse R (2010) Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6:568–577PubMedCentralPubMedGoogle Scholar
  129. 129.
    Lowell S, Benchoua A, Heavey B, Smith AG (2006) Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol 4:e121PubMedCentralPubMedGoogle Scholar
  130. 130.
    Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M (2006) Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 12:89–98PubMedGoogle Scholar
  131. 131.
    Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ (2012) Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18:572–579PubMedCentralPubMedGoogle Scholar
  132. 132.
    Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, Roskams T (2010) Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 59:247–257PubMedGoogle Scholar
  133. 133.
    Ayyanan A, Civenni G, Ciarloni L, Morel C, Mueller N, Lefort K, Mandinova A, Raffoul W, Fiche M, Dotto GP, Brisken C (2006) Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci USA 103:3799–3804PubMedCentralPubMedGoogle Scholar
  134. 134.
    Collu GM, Brennan K (2007) Cooperation between Wnt and Notch signalling in human breast cancer. Breast Cancer Res 9:105PubMedCentralPubMedGoogle Scholar
  135. 135.
    Fre S, Pallavi SK, Huyghe M, Lae M, Janssen KP, Robine S, Artavanis-Tsakonas S, Louvard D (2009) Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 106:6309–6314PubMedCentralPubMedGoogle Scholar
  136. 136.
    Gonsalves FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S, Nagourney R, Cardozo T, Brown AM, DasGupta R (2011) An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc Natl Acad Sci USA 108:5954–5963PubMedCentralPubMedGoogle Scholar
  137. 137.
    Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107PubMedCentralPubMedGoogle Scholar
  138. 138.
    Arcaroli JJ, Quackenbush KS, Purkey A, Powell RW, Pitts TM, Bagby S, Tan AC, Cross B, McPhillips K, Song EK, Tai WM, Winn RA, Bikkavilli K, Vanscoyk M, Eckhardt SG, Messersmith WA (2013) Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a gamma-secretase inhibitor, in a preclinical colorectal explant model. Br J Cancer 109:667–675PubMedCentralPubMedGoogle Scholar
  139. 139.
    Heath JK (2010) Transcriptional networks and signaling pathways that govern vertebrate intestinal development. Curr Top Dev Biol 90:159–192PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Giovanna M. Collu
    • 1
    • 2
  • Ana Hidalgo-Sastre
    • 1
    • 3
  • Keith Brennan
    • 1
    Email author
  1. 1.Faculty of Life SciencesUniversity of ManchesterManchesterUK
  2. 2.Department of Developmental & Regenerative BiologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.II Medizinische Klinik, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

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