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.

  • Review
  • Published:

Wnt signalling in the mouse intestine

Oncogene volume 25, pages 7512–7521 (2006)Cite this article

Abstract

The ApcMin/+ mouse has emerged as a powerful model of human intestinal tumour predisposition. As such, it has provided a platform for studying genetic and epigenetic modifiers of adenoma predisposition, and for assessing the chemotherapeutic potential of a plethora of different agents. The development of new conditional and hypomorphic Apc alleles, together with models carrying mutations in other Wnt pathway components, has greatly extended the scope of experimentation. Together these approaches are being used to identify and validate key critical targets of the Wnt pathway, such as Mash2, Tiam1 and the Eph/Ephrins. They have also established a fundamental role for Wnt in the development and maintenance of normal intestinal physiology, and in particular control of the stem cell niche. These activities are now being dissected at the level of individual Wnt components, with some surprising dependencies revealed. In terms of adenoma development, these models also support a ‘just right’ notion for tightly controlled β-catenin activity both in normal physiology and neoplastic development. They also indicate a two-stage dependency for some Wnt pathway targets, with an initial requirement that is subsequently overcome to permit progression. Finally, these models establish that the Wnt pathway does not operate in isolation, and that both normal and diseased physiology develops in a dynamic interplay with other pathways such as the Notch, Hedgehog and BMP pathways. The comprehensive understanding arising from these studies should lead the identification of novel prognostic markers and therapeutic targets, and also open the possibility of tissue engineering in the intestine.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  • Andreu P, Colnot S, Godard C, Gad S, Chafey P, Niwa-Kawakita M et al. (2005). Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132: 1443–1451.

    Article  CAS  PubMed  Google Scholar 

  • Alberici P, Jagmohan-Changur S, De Pater E, Van Der Valk M, Smits R, Hohenstein P et al. (2006). Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene 25: 1841–1851.

    Article  CAS  PubMed  Google Scholar 

  • Albuquerque C, Breukel C, van der Luijt R, Fidalgo P, Lage P, Slors FJ et al. (2002). The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 11: 1549–1560.

    Article  CAS  PubMed  Google Scholar 

  • Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G et al. (2002). Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling expression of EphB/ephrinB. Cell 111: 251–263.

    Article  CAS  PubMed  Google Scholar 

  • Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M et al. (2005). EphB receptor activity suppresses colorectal cancer progression. Nature 435: 1126–1130.

    Article  CAS  PubMed  Google Scholar 

  • Bettess MD, Dubois N, Murphy MJ, Dubey C, Roger C, Robine S et al. (2005). C-Myc is required for the formation of intestinal crypts but dispensible for homeostasis of the adult intestinal epithelium. Mol Cell Biol 25: 7868–7878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blache P, van der Wetering M, Duluc I, Domon C, Berta P, Freund JN et al. (2004). SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166: 33–47.

    Article  Google Scholar 

  • Chia IV, Costantini F . (2005). Mouse axin and axin2/conductin proteins are functionally equivalent in vivo. Mol Cell Biol 25: 4371–4376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corpet DE, Pierre F . (2003). From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomark Prevent 12: 391–400.

    Google Scholar 

  • Corpet DE, Pierre F . (2005). How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer 41: 1911–1922.

    Article  CAS  PubMed  Google Scholar 

  • Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB et al. (2005). Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 7: 545–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C et al. (1993). Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75: 631–639.

    Article  CAS  PubMed  Google Scholar 

  • Dorudi S, Sheffield JP, Poulsom R, Northover JM, Hart IR . (1993). E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am J Pathol 142: 981–986.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eads CA, Nickel AE, Laird PW . (2002). Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in ApcMin/+ Dnmt1-hypomorphic mice. Cancer Res 62: 1296–1299.

    CAS  PubMed  Google Scholar 

  • Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C et al. (2001). Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3: 433–438.

    Article  CAS  PubMed  Google Scholar 

  • Galceran J, Farinas I, Depew MJ, Clevers H, Grosschedl R . (1999). Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice. Genes Dev 13: 709–717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giannakis M, Stappenbeck TS, Mills JC, Leip DG, Lovett M, Clifton SW et al. (2006). Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem 281: 11292–11300.

    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 

  • Gregorieff A, Grosschedl R, Clevers H . (2004). Hindgut defects and transformation of the gastrointestinal tract in Tcf4-/-Tcf1-/- embryos. EMBO J 23: 1825–1833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregorieff A, Pinto D, Begthel H, Destree O, Kielman M, Clevers H . (2005). Expression pattern of Wnt signalling components in the adult intestine. Gastroenterology 129: 626–638.

    Article  CAS  PubMed  Google Scholar 

  • Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M et al. (2003). Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4: 111–120.

    Article  CAS  PubMed  Google Scholar 

  • Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN . (2004). Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Nat Med 10: 245–247.

    Article  CAS  PubMed  Google Scholar 

  • Hadjihannas MV, Bruckner M, Jerchow B, Birchmeier W, Dietmaier M, Behrens J . (2006). Aberrant Wnt/beta-catenin signalling can induce chromosomal instability in colon cancer. Proc Natl Acad Sci USA 103: 10747–10752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haines J, Johnson V, Pack K, Suraweera N, Slijepcevic P, Cabuy E et al. (2005). Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice. Proc Natl Acad Sci USA 102: 2868–2873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E et al. (2006). Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124: 47–59.

    Article  CAS  PubMed  Google Scholar 

  • Hamamoto T, Beppu H, Okada H, Kawabata M, Kitamura T, Miyazono K et al. (2002). Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice. Cancer Res 62: 5955–5961.

    CAS  PubMed  Google Scholar 

  • Hao J, Li TG, Qi X, Zhao DF, Zhao GQ . (2006). Wnt/beta-catenin pathway upregulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells. Dev Biol 290: 81–91.

    Article  CAS  PubMed  Google Scholar 

  • Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M et al. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 18: 5931–5942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haramis AP, Begthel H, van den Born M, van Es J, Jonkheer S, Offerhaus GJ et al. (2004). De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303: 1684–1686.

    Article  CAS  PubMed  Google Scholar 

  • Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, Peters JM . (2004). Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 10: 481–483.

    Article  CAS  PubMed  Google Scholar 

  • He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH et al. (2004). BMP signalling inhibits intestinal stem cell self-renewal through suppression of Wnt-b-catenin signalling. Nat Genet 36: 1117–1121.

    Article  CAS  PubMed  Google Scholar 

  • Hochedlinger K, Yamada Y, Beard C, Jaenisch R . (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121: 463–477.

    Article  CAS  Google Scholar 

  • Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ et al. (2006). EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125: 1151–1163.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh M, Boerboom D, Shimada M, Lo Y, Parlow AF, Luhmann UF et al. (2005). Mice null fro frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea formation and function. Biol Reprod 73: 1135–1146.

    Article  CAS  PubMed  Google Scholar 

  • Hulit J, Wang C, Li Z, Albanese C, Rao M, Di Vizio D et al. (2004). Cyclin D1 genetic heterozygosity regulates colonic cell differentiation and tumor number in ApcMin mice. Mol Cell Biol 24: 7598–7611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ireland H, Kemp R, Houghton C, Howard L, Clarke AR, Sansom OJ et al. (2004). Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of β-catenin. Gasteroenterology 126: 1236–1246.

    Article  CAS  Google Scholar 

  • Janssen KP, el-Marjou F, Pinto D, Sastre X, Rouillard D, Fourquet C et al. (2002). Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice. Gastroenterology 123: 492–504.

    Article  CAS  PubMed  Google Scholar 

  • Jubb AM, Chalasani S, Frantz GD, Smits R, Grabsch HI, Kavi V et al. (2006). Achaete-scute like 2(ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia. Oncogene 25: 3445–3457.

    Article  CAS  PubMed  Google Scholar 

  • Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS . (2001). A role for the adenomatous polyposis coli protein in chromosome segregation. Nat Cell Biol 3: 429–432.

    Article  CAS  PubMed  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 

  • 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 

  • Kielman MF, Rindapaa M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S et al. (2002). Apc modulates embryonic stem cell differentiation by controlling the dosage of beta-catenin signalling. Nat Genet 32: 594–605.

    Article  CAS  PubMed  Google Scholar 

  • Kim BM, Buchner G, Miletich I, Sharpe PT, Shivdasani RA . (2005a). The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signalling. Cev Cell 8: 611–622.

    CAS  Google Scholar 

  • Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M et al. (2005b). Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 309: 1256–1259.

    Article  CAS  PubMed  Google Scholar 

  • Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ et al. (1998). Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19: 379–383.

    Article  CAS  PubMed  Google Scholar 

  • Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J et al. (2004). Essential requirement for Wnt signalling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci USA 101: 266–271.

    Article  CAS  PubMed  Google Scholar 

  • Leung SY, Chen X, Chu KM, Yuen ST, Mathy J, Ji J et al. (2002). Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis. Proc Natl Acad Sci USA 99: 16203–16208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Ishikawa TO, Oshima M, Taketo MM . (2005). The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenseis. Cancer Res 65: 8622–8627.

    Article  CAS  PubMed  Google Scholar 

  • Lickert H, Domon C, Huls G, Wehrle C, Duluc I, Clevers H et al. (2000). Wnt/(beta)-catenin signalling regulates the expression of the homeobox gene Cdx1 in embryonic intestine. Development 127: 3805–3813.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM . (1995). The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81: 957–966.

    Article  CAS  PubMed  Google Scholar 

  • Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL . (2005). Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132: 279–289.

    Article  CAS  PubMed  Google Scholar 

  • Mariadason JM, Nicholas C, L'Italien KE, Zhuang M, Smartt HJ, Heerdt BG et al. (2005). Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis. Gastroenterology 128: 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  • Malliri A, Rygiel TP, van der Kammen RA, Song JY, Engers R, Hurlstone AF et al. (2006). The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumour development. J Biol Chem 281: 543–548.

    Article  CAS  PubMed  Google Scholar 

  • Milano J, McKay J, Dagenais C, Foster-Brown L, Pogan F, Gadient R et al. (2004). Modulation of notch processing by gamma secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82: 341–358.

    Article  CAS  PubMed  Google Scholar 

  • Mills JC, Andersson N, Hong CV, Stappenbeck TS, Gordon JI . (2002). Molecular characterisation of mouse gastric epithelial progenitor cells. Gastroenterology 125: 266–267.

    Google Scholar 

  • Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B et al. (2002). Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297: 403–405.

    Article  CAS  PubMed  Google Scholar 

  • Muncan V, Sansom OJ, Tertoolen L, Phesse TJ, Begthel H, Sancho E et al. (2006). Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol Cell Biol [E-pub 5 September 2006], doi: 10.1128/MCB.00821-06 [Abstract].

  • Nateri AS, Spencer-Dene B, Behrens A . (2005). Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437: 281–285.

    Article  CAS  PubMed  Google Scholar 

  • Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H . (2006). Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 343: 159–166.

    Article  CAS  PubMed  Google Scholar 

  • Ormestad M, Astorga J, Landgren H, Wang T, Johansson BR, Miura N et al. (2006). Foxf1 and Foxf2 control murine gut development by liming mesenchymal Wnt signalling and promoting extracellular matrix production. Development 133: 833–843.

    Article  CAS  PubMed  Google Scholar 

  • Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M . (1995). Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA 92: 4482–4486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perreault N, Sackett SD, Katz JP, Furth EE, Kaestner KH . (2005). Foxl1 is a mesenchymal modifier of Min in carcinogenesis of stomach and colon. Genes Dev 19: 311–315.

    Article  CAS  PubMed  PubMed Central  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 

  • Pinto D, Gregorieff A, Begthel H, Clevers H . (2003). Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17: 1709–1713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prokhortchouk A, Sansom OJ, Selfridge J, Hendrich B, Caballero IM, Salozhin S et al. (2006). Kaiso-deficient mice show resistance to intestinal cancer. Mol Cell Biol 26: 199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pretlow TP, Edelmann W, Kucherlapati R, Pretlow TG, Augenlicht LH . (2003). Spontaneous aberrant crypt foci in Apc1638N mice with a mutant Apc allele. Am J Pathol 163: 1757–1763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao CV, Yang YM, Swarmy MV, Liu T, Fang Y, Mahmood R et al. (2005). Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci USA 102: 4365–4370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reed KR, Sansom OJ, Hayes AJ, Gescher AJ, Winton DJ, Peters JM et al. (2004). PPARδ status and Apc mediated tumourigenesis in the mouse intestine. Oncogene 23: 8992–8996.

    Article  CAS  PubMed  Google Scholar 

  • Reichling T, Goss KH, Carson DJ, Holdcraft RW, Ley-Ebert C, Witte D et al. (2005). Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors. Cancer Res 65: 166–176.

    CAS  PubMed  Google Scholar 

  • Reitmair AH, Cai JC, Bjerknes M, Redston M, Cheng H, Pind MT et al. (1996). MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res 56: 2922–2926.

    CAS  PubMed  Google Scholar 

  • Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH . (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10: 55–63.

    Article  CAS  PubMed  Google Scholar 

  • Sakatani T, Kaneda A, Iacobuzio-Donahue CA, Carter MG, de Boom Witzel S, Okano H et al. (2005). Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307: 1976–1978.

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke AR . (2003). Deficiency of the DNA methylation-dependent transcriptional repressor Mbd2 suppresses intestinal tumourigenesis. Nat Genet 34: 145–147.

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ, Reed K, Hayes AJ, Ireland H, Brinkmann H, Newton IP et al. (2004). Loss of Apc immediately perturbs differentiation and migration in the small intestine. Genes Dev 18: 1385–1390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sansom OJ, Reed KR, van de Wetering M, Muncan V, Winton DJ, Clevers H et al. (2005). Cyclin D1 is not an immediate target of beta-catenin following Apc loss in the intestine. J Biol Chem 280: 28463–28467.

    Article  CAS  PubMed  Google Scholar 

  • Sansom OJ, Meniel V, Wilkins JA, Cole A, Oien K, Jamieson T et al. (2006). Endogenous oncogenic K-ras does not alter intestinal homeostasis, but enhances the delayed consequences of Apc loss. Proc Natl Acad Sci USA 103: 14122–14127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sieber OM, Howarth KM, Thirlwell C, Rowan A, Mandir N, Goodlad RA et al. (2004). Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice. Cancer Res 64: 8876–8881.

    Article  CAS  PubMed  Google Scholar 

  • Silverman KA, Koratkar R, Siracusa LD, Buchberg AM . (2002). Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Res 12: 88–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singla DK, Schneider DJ, LeWinter MM, Sobel BE . (2006). Wnt3a but not wnt11 supports self renewal of embryonic stem cells. Biochem Biophys Res Commun 345: 789–795.

    Article  CAS  PubMed  Google Scholar 

  • Smits R, Kartheuser A, Jagmohan-Changur S, Leblanc V, Breukel C, de Vries A et al. (1997). Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis. Carcinogenesis 18: 321–327.

    Article  CAS  PubMed  Google Scholar 

  • Smits R, Ruiz P, Diaz-Cano S, Luz A, Jagmohan-Changur S, Breukel C et al. (2000). E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice. Gastroenterology 119: 1045–1053.

    Article  CAS  PubMed  Google Scholar 

  • Spring CM, Kelly KF, O'Kelly I, Graham M, Crawford HC, Daniel JM . (2005). The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the beta-catenin/TCF target gene matrilysin. Exp Cell Res 305: 253–265.

    Article  CAS  PubMed  Google Scholar 

  • Stappenbeck TS, Mills JC, Gordon JI . (2003). Molecular features of adult mouse small intestinal epithelial progenitors. Proc Natl Acad Sci USA 100: 1004–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C et al. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256: 668–670.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al. (2004). Epigenetic inactivation of SFRP genes allows constitutive WNT signalling in colon cancer. Nat Genet 36: 417–422.

    Article  CAS  PubMed  Google Scholar 

  • Takano-Maruyama M, Hase K, Fukamachi H, Kato Y, Koseki H, Ohno H . (2006). Foxl1-deficient mice exhibit aberrant epithelial cell positioning resulting from dysregulated EphB/EphrinB expression in the small intestine. Am J Physiol Gastrointest Liver Physiol 291: G163–70.

    Article  CAS  PubMed  Google Scholar 

  • Takaku K, Miyoshi H, Matsunaga A, Oshima M, Sasaki N, Taketo MM . (1999). Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res 59: 6113–6117.

    CAS  PubMed  Google Scholar 

  • Trinh BN, Long TI, Nickel AE, Shibata D, Laird PW . (2002). DNA methylytransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. Mol Cell Biol 22: 2906–2917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Amerongen R, Nawijn M, Franca-Koh J, Zevenhoven J, van der Gulden H, Jonkers J et al. (2005). Frat is dispensible for canonical Wnt signalling in mammals. Genes Dev 19: 425–430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van den Brink GR, Bleuming SA, Hardwick JC, Schepman BL, Offerhaus GJ, Keller JJ et al. (2004). Indian Hedgehog is an antagonist of Wnt signalling in colonic epithelial cell differentiation. Nat Genet 36: 277–282.

    Article  CAS  PubMed  Google Scholar 

  • Van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cells. Cell 111: 241–250.

    Article  CAS  PubMed  Google Scholar 

  • Van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P et al. (2005a). Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7: 381–386.

    Article  CAS  PubMed  Google Scholar 

  • Van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H et al. (2005b). Notch/gamma secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963.

    Article  CAS  PubMed  Google Scholar 

  • Wilding J, Straub J, Bee J, Churchman M, Bodmer W, Dickson C et al. (2002). Cyclin D1 is not an essential target of beta-catenin signaling during intestinal tumorigenesis, but it may act as a modifier of disease severity in multiple intestinal neoplasia (Min) mice. Cancer Res 62: 4562–4565.

    CAS  PubMed  Google Scholar 

  • Wong MH, Rubinfeld B, Gordon JI . (1998). Effects of forced expression of an NH2-terminal truncated beta-catenin on mouse intestinal epithelial homeostasis. J Cell Biol 141: 765–777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong MH, Huelsken J, Birchmeier W, Gordon JI . (2002). Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkuhn is perturbed by stimulation of Lef-1/beta-catenin signalling. J Biol Chem 277: 15843–15850.

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Brodie SG, Yang X, Im YH, Parks WT, Chen L et al. (2000). Haploid loss of the tumour suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19: 1868–1874.

    Article  CAS  PubMed  Google Scholar 

  • Yamada Y, Jackson Grusby L, Linhart H, Meissner A, Eden A, Lin H et al. (2005). Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 102: 13580–13585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zecchini V, Domaschenz R, Winton D, Jones P . (2005). Notch signalling regulates the differentiation of post-mitotic intestinal epithelial cells. Genes Dev 19: 1686–1691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Chen X, Kato Y, Evans PM, Yuan S, Yang J et al. (2006). Novel cross talk of Kruppel-like factor 4 and beta catenin regulates normal intestinal homeostasis and tumor repression. Mol Cell Biol 26: 2055–2064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu P, Martin E, Mengwesser J, Schlag P, Janssen KP, Gottlicher M . (2004). Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5: 455–463.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiff School of Biosciences, Museum Avenue, Cardiff University, Cardiff, UK

    A R Clarke

Authors
  1. A R Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A R Clarke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clarke, A. Wnt signalling in the mouse intestine. Oncogene 25, 7512–7521 (2006). https://doi.org/10.1038/sj.onc.1210065

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210065

Keywords

This article is cited by

Search

Advanced search

Quick links