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Transgenic Wnt/TCF pathway reporters: all you need is Lef?

Oncogene volume 25, pages 7505–7511 (2006)Cite this article

Abstract

The Wnt signaling pathway controls a large and diverse set of cell fate decisions in embryonic development, adult organ maintenance and disease. At the transcriptional level, Wnt/β-catenin signaling is primarily mediated by the T-cell factor (TCF)/Lef-1 family of transcription factors, referred to here as TCFs. In order to track Wnt pathway activity during animal development, several laboratories have built transgenic reporter constructs containing multimerized TCF binding sites. Most of these reporters are active at multiple known sites of Wnt signaling, and several act as faithful reporters of pathway activity in specific contexts. However, multimerized TCF reporters should not be assumed to give a complete or definitive readout of Wnt signaling in vivo. Direct comparisons reveal discrepancies among reporters; in addition, there is good reason to expect that some important types of pathway activity, including target gene de-repression and TCF-independent Wnt or β-catenin signaling, will not be accurately reported by such constructs. This review will discuss various transgenic Wnt/β-catenin/TCF reporters, address the fidelity and completeness of their Wnt responsiveness, and contrast their in vivo transcriptional responses with those of natural Wnt target genes. Finally, three caveats to the interpretation of multimerized TCF reporter expression patterns will be proposed.

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References

  • Arnold SJ, Stappert J, Bauer A, Kispert A, Herrmann BG, Kemler R . (2000). Brachyury is a target gene of the Wnt/β-catenin signaling pathway. Mech Dev 91: 249–258.

    Article  CAS  Google Scholar 

  • Barolo S, Carver LA, Posakony JW . (2000). GFP and β-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. Biotechniques 29: 726–732.

    Article  CAS  Google Scholar 

  • Barolo S, Posakony JW . (2002). Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev 16: 1167–1181.

    Article  CAS  Google Scholar 

  • Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D . (1997). A β-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev 11: 2359–2370.

    Article  CAS  Google Scholar 

  • Brantjes H, Roose J, van De Wetering M, Clevers H . (2001). All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res 29: 1410–1419.

    Article  CAS  Google Scholar 

  • Carr M, Hurley I, Fowler K, Pomiankowski A, Smith HK . (2005). Expression of defective proventriculus during head capsule development is conserved in Drosophila and stalk-eyed flies (Diopsidae). Dev Genes Evol 215: 402–409.

    Article  Google Scholar 

  • Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H et al. (1998). Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395: 604–608.

    Article  CAS  Google Scholar 

  • Chen AE, Ginty DD, Fan CM . (2005). Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins. Nature 433: 317–322.

    Article  CAS  Google Scholar 

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P et al. (1999). The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors. Oncogene 18: 2883–2891.

    Article  CAS  Google Scholar 

  • DasGupta R, Fuchs E . (1999). Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126: 4557–4568.

    CAS  PubMed  Google Scholar 

  • De Langhe SP, Sala FG, Del Moral PM, Fairbanks TJ, Yamada KM, Warburton D et al. (2005). Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lung. Dev Biol 277: 316–331.

    Article  CAS  Google Scholar 

  • Denayer T, Van Roy F, Vleminckx K . (2006). In vivo tracing of canonical Wnt signaling in Xenopus tadpoles by means of an inducible transgenic reporter tool. FEBS Lett 580: 393–398.

    Article  CAS  Google Scholar 

  • Dessimoz J, Bonnard C, Huelsken J, Grapin-Botton A . (2005). Pancreas-specific deletion of β-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr Biol 15: 1677–1683.

    Article  CAS  Google Scholar 

  • Dorsky RI, Sheldahl LC, Moon RT . (2002). A transgenic Lef1/β-catenin-dependent reporter is expressed in spatially restricted domains throughout zebrafish development. Dev Biol 241: 229–237.

    Article  CAS  Google Scholar 

  • Fathke C, Wilson L, Shah K, Kim B, Hocking A, Moon R et al. (2006). Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol 7: 4.

    Article  Google Scholar 

  • Filali M, Cheng N, Abbott D, Leontiev V, Engelhardt JF . (2002). Wnt-3A/β-catenin signaling induces transcription from the LEF-1 promoter. J Biol Chem 277: 33398–33410.

    Article  CAS  Google Scholar 

  • Geng X, Xiao L, Lin GF, Hu R, Wang JH, Rupp RA et al. (2003). Lef/Tcf-dependent Wnt/β-catenin signaling during Xenopus axis specification. FEBS Lett 547: 1–6.

    Article  CAS  Google Scholar 

  • Giese K, Kingsley C, Kirshner JR, Grosschedl R . (1995). Assembly and function of a TCRα enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev 9: 995–1008.

    Article  CAS  Google Scholar 

  • Halfon MS, Carmena A, Gisselbrecht S, Sackerson CM, Jimenez F, Baylies MK et al. (2000). Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell 103: 63–74.

    Article  CAS  Google Scholar 

  • Hatini V, DiNardo S . (2001). Distinct signals generate repeating striped pattern in the embryonic parasegment. Mol Cell 7: 151–160.

    Article  CAS  Google Scholar 

  • Haynes TL, Thomas MB, Dusing MR, Valerius MT, Potter SS, Wiginton DA . (1996). An enhancer LEF-1/TCF-1 site is essential for insertion site-independent transgene expression in thymus. Nucleic Acids Res 24: 5034–5044.

    Article  CAS  Google Scholar 

  • Hecht A, Kemler R . (2000). Curbing the nuclear activities of beta-catenin. EMBO Rep 1: 24–28.

    Article  CAS  Google Scholar 

  • Hernandez-Munain C, Roberts JL, Krangel MS . (1998). Cooperation among multiple transcription factors is required for access to minimal T-cell receptor α-enhancer chromatin in vivo. Mol Cell Biol 18: 3223–3233.

    Article  CAS  Google Scholar 

  • Hsu SC, Galceran J, Grosschedl R . (1998). Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with β-catenin. Mol Cell Biol 18: 4807–4818.

    Article  CAS  Google Scholar 

  • Hurlstone AF, Haramis AP, Wienholds E, Begthel H, Korving J, Van Eeden F et al. (2003). The Wnt/β-catenin pathway regulates cardiac valve formation. Nature 425: 633–637.

    Article  CAS  Google Scholar 

  • Jamora C, DasGupta R, Kocieniewski P, Fuchs E . (2003). Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422: 317–322.

    Article  CAS  Google Scholar 

  • Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F . (2002). Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22: 1172–1183.

    Article  CAS  Google Scholar 

  • Jian H, Shen X, Liu I, Semenov M, He X, Wang XF . (2006). Smad3-dependent nuclear translocation of β-catenin is required for TGF-β1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20: 666–674.

    Article  CAS  Google Scholar 

  • Kassis JA, Noll E, VanSickle EP, Odenwald WF, Perrimon N . (1992). Altering the insertional specificity of a Drosophila transposable element. Proc Natl Acad Sci USA 89: 1919–1923.

    Article  CAS  Google Scholar 

  • Knirr S, Frasch M . (2001). Molecular integration of inductive and mesoderm-intrinsic inputs governs even-skipped enhancer activity in a subset of pericardial and dorsal muscle progenitors. Dev Biol 238: 13–26.

    Article  CAS  Google Scholar 

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. (1997). Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma. Science 275: 1784–1787.

    Article  CAS  Google Scholar 

  • Labbé E, Letamendia A, Attisano L . (2000). Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-β and Wnt pathways. Proc Natl Acad Sci USA 97: 8358–8363.

    Article  Google Scholar 

  • Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S et al. (2002). Activation of AXIN2 expression by β-catenin-T cell factor. J Biol Chem 277: 21657–21665.

    Article  CAS  Google Scholar 

  • Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437: 1370–1375.

    Article  CAS  Google Scholar 

  • Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U et al. (2002). Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22: 1184–1193.

    Article  CAS  Google Scholar 

  • Maduro MF, Kasmir JJ, Zhu J, Rothman JH . (2005). The Wnt effector POP-1 and the PAL-1/Caudal homeoprotein collaborate with SKN-1 to activate C. elegans endoderm development. Dev Biol 285: 510–523.

    Article  CAS  Google Scholar 

  • Maretto S, Cordenonsi M, Dupont S, Braghetta P, Broccoli V, Hassan AB et al. (2003). Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci USA 100: 3299–3304.

    Article  CAS  Google Scholar 

  • Merrill BJ, Gat U, DasGupta R, Fuchs E . (2001). Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev 15: 1688–1705.

    Article  CAS  Google Scholar 

  • Merrill BJ, Pasolli HA, Polak L, Rendl M, Garcia-Garcia MJ, Anderson KV et al. (2004). Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131: 263–274.

    Article  CAS  Google Scholar 

  • Mohamed OA, Clarke HJ, Dufort D . (2004). β-Catenin signaling marks the prospective site of primitive streak formation in the mouse embryo. Dev Dyn 231: 416–424.

    Article  CAS  Google Scholar 

  • Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, Yamaguchi TP . (2005). Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development 132: 5425–5436.

    Article  CAS  Google Scholar 

  • Newfeld SJ, Takaesu NT . (2002). An analysis using the hobo genetic system reveals that combinatorial signaling by the Dpp and Wg pathways regulates dpp expression in leading edge cells of the dorsal ectoderm in Drosophila melanogaster. Genetics 161: 685–692.

    CAS  PubMed  PubMed Central  Google Scholar 

  • O'Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S et al. (2004). Glycogen synthase kinase-3β haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 24: 6791–6798.

    Article  CAS  Google Scholar 

  • Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K et al. (2005). Kaiso/p120-catenin and TCF/β-catenin complexes coordinately regulate canonical Wnt gene targets. Dev Cell 8: 843–854.

    Article  CAS  Google Scholar 

  • Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC et al. (2004). Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells. Oncogene 23: 3689–3699.

    Article  CAS  Google Scholar 

  • Prieve MG, Waterman ML . (1999). Nuclear localization and formation of β-catenin-lymphoid enhancer factor 1 complexes are not sufficient for activation of gene expression. Mol Cell Biol 19: 4503–4515.

    Article  CAS  Google Scholar 

  • Riese J, Yu X, Munnerlyn A, Eresh S, Hsu SC, Grosschedl R et al. (1997). LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic. Cell 88: 777–787.

    Article  CAS  Google Scholar 

  • Robertson LM, Kerppola TK, Vendrell M, Luk D, Smeyne RJ, Bocchiaro C et al. (1995). Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements. Neuron 14: 241–252.

    Article  CAS  Google Scholar 

  • Romani S, Campuzano S, Macagno ER, Modolell J . (1989). Expression of achaete and scute genes in Drosophila imaginal discs and their function in sensory organ development. Genes Dev 3: 997–1007.

    Article  CAS  Google Scholar 

  • Roose J . (1999). HMG box transcription factors in development. PhD dissertation, University Hospital Utrecht, The Netherlands.

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R et al. (1999). The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 275: 21203–21209.

    Google Scholar 

  • Shu W, Guttentag S, Wang Z, Andl T, Ballard P, Lu MM et al. (2005). Wnt/β-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol 283: 226–239.

    Article  CAS  Google Scholar 

  • Spychala J, Zimmermann AG, Mitchell BS . (1999). Tissue-specific regulation of the ecto-5′-nucleotidase promoter. Role of the cAMP response element site in mediating repression by the upstream regulatory region. J Biol Chem 274: 22705–22712.

    Article  CAS  Google Scholar 

  • Staal FJ, Meeldijk J, Moerer P, Jay P, van de Weerdt BC, Vainio S et al. (2001). Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur J Immunol 31: 285–293.

    Article  CAS  Google Scholar 

  • Staal FJ, Weerkamp F, Baert MR, van den Burg CM, van Noort M, de Haas EF et al. (2004). Wnt target genes identified by DNA microarrays in immature CD34+ thymocytes regulate proliferation and cell adhesion. J Immunol 172: 1099–1108.

    Article  CAS  Google Scholar 

  • Theil T, Aydin S, Koch S, Grotewold L, Rüther U . (2002). Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development 129: 3045–3054.

    CAS  PubMed  Google Scholar 

  • van Beest M, Dooijes D, van De Wetering M, Kjaerulff S, Bonvin A, Nielsen O et al. (2000). Sequence-specific high mobility group box factors recognize 10–12-base pair minor groove motifs. J Biol Chem 275: 27266–27273.

    CAS  PubMed  Google Scholar 

  • Volk T, VijayRaghavan K . (1994). A central role for epidermal segment border cells in the induction of muscle patterning in the Drosophila embryo. Development 120: 59–70.

    CAS  PubMed  Google Scholar 

  • Watabe T, Kim S, Candia A, Rothbacher U, Hashimoto C, Inoue K et al. (1995). Molecular mechanisms of Spemann's organizer formation: conserved growth factor synergy between Xenopus and mouse. Genes Dev 9: 3038–3050.

    Article  CAS  Google Scholar 

  • Wilson C, Pearson RK, Bellen HJ, O'Kane CJ, Grossniklaus U, Gehring WJ . (1989). P-element-mediated enhancer detection: an efficient method for isolating and characterizing developmentally regulated genes in Drosophila. Genes Dev 3: 1301–1313.

    Article  CAS  Google Scholar 

  • Yang X, van Beest M, Clevers H, Jones T, Hursh DA, Mortin MA . (2000). Decapentaplegic is a direct target of dTcf repression in the Drosophila visceral mesoderm. Development 127: 3695–3702.

    CAS  PubMed  Google Scholar 

  • Yu X, Riese J, Eresh S, Bienz M . (1998). Transcriptional repression due to high levels of Wingless signalling. EMBOJ 17: 7021–7032.

    Article  CAS  Google Scholar 

  • Ziemer LT, Pennica D, Levine AJ . (2001). Identification of a mouse homolog of the human BTEB2 transcription factor as a β-catenin-independent Wnt-1-responsive gene. Mol Cell Biol 21: 562–574.

    Article  CAS  Google Scholar 

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Acknowledgements

I am very grateful to the following researchers for generously sharing their insights, opinions and/or unpublished observations: Travis Biechele, Mariann Bienz, Ken Cadigan, Hans Clevers, Elaine Fuchs, Randy Moon, Roel Nusse, Jim Posakony, Jeroen Roose, Chris Thorpe and Gilbert Weidinger. Rich Dorsky and Brad Merrill were exceptionally helpful, providing thoughtful and detailed responses to my questions.

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  1. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA

    S Barolo

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Barolo, S. Transgenic Wnt/TCF pathway reporters: all you need is Lef?. Oncogene 25, 7505–7511 (2006). https://doi.org/10.1038/sj.onc.1210057

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