TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex
Open accessAbstract
BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tbx3 acts as a target of Wnts in other contexts.
“These findings agree with Tbx3 acting as a target of Wnts in other contexts (25, 27–30).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [30]
The Results and discussion describe TBX3 as a regulator of Wnt target genes, but do not say that TBX3 itself is a target of Wnts in other contexts. Searches for TBX3 as a Wnt target and for Wnt-dependent TBX3 expression found no passage addressing that direction of regulation. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 40 · Cited by 47
Research works printed but not linked: 36
- Barker N van Es JH Kuipers J Kujala P van den Born M Cozijnsen M Haegebarth A Korving J Begthel H Peters PJ Clevers H 2007 Identification of stem cells in small intestine and Colon by marker gene Lgr5 Nature 449 1003 1007 10.1038/nature06196 17934449 · DOI · Paper page
- Cantù C Valenta T Hausmann G Vilain N Aguet M Basler K 2013 The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and wnt signaling-dependent transcription Development 140 2377 2386 10.1242/dev.093591 23637336 · DOI
- Cantù C Zimmerli D Hausmann G Valenta T Moor A Aguet M Basler K 2014 Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse Lens development Genes & Development 28 1879 1884 10.1101/gad.246140.114 25184676 PMC4197948 · DOI
- Cantù C Pagella P Shajiei TD Zimmerli D Valenta T Hausmann G Basler K Mitsiadis TA 2017 A cytoplasmic role of wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation Science Signaling 10 1 11 10.1126/scisignal.aah4598 28174279 · DOI
- Cantù C Felker A Zimmerli D Prummel KD Cabello EM Chiavacci E Méndez-Acevedo KM Kirchgeorg L Burger S Ripoll J Valenta T Hausmann G Vilain N Aguet M Burger A Panáková D Basler K Mosimann C 2018 Mutations in Bcl9 and pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling Genes & Development 32 1443 1458 10.1101/gad.315531.118 30366904 PMC6217730 · DOI
- Capdevila J Tsukui T Rodríquez Esteban C Zappavigna V Izpisúa Belmonte JC 1999 Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by gremlin Molecular Cell 4 839 849 10.1016/S1097-2765(00)80393-7 10619030 · DOI
- Deka J Wiedemann N Anderle P Murphy-Seiler F Bultinck J Eyckerman S Stehle JC André S Vilain N Zilian O Robine S Delorenzi M Basler K Aguet M 2010 Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in Colon epithelium and adenocarcinomas Cancer Research 70 6619 6628 10.1158/0008-5472.CAN-10-0148 20682801 · DOI
- Doumpas N Lampart F Robinson MD Lentini A Nestor CE Cantù C Basler K 2019 TCF/LEF dependent and independent transcriptional regulation of wnt/β-catenin target genes The EMBO Journal 38 e98873 10.15252/embj.201798873 30425074 PMC6331726 · DOI
- Fiedler M Graeb M Mieszczanek J Rutherford TJ Johnson CM Bienz M 2015 An ancient Pygo-dependent wnt enhanceosome integrated by chip/LDB-SSDP eLife 4 e09073 10.7554/eLife.09073 PMC4571689 26312500 · DOI
- Gay DM Ridgway RA Müeller M Hodder MC Hedley A Clark W Leach JD Jackstadt R Nixon C Huels DJ Campbell AD Bird TG Sansom OJ 2019 Loss of BCL9/9l suppresses wnt driven tumourigenesis in models that recapitulate human Cancer Nature Communications 10 1 16 10.1038/s41467-019-08586-3 PMC6374445 30760720 · DOI
- Grifone R Demignon J Giordani J Niro C Souil E Bertin F Laclef C Xu PX Maire P 2007 Eya1 and Eya2 proteins are required for hypaxial somitic myogenesis in the mouse embryo Developmental Biology 302 602 616 10.1016/j.ydbio.2006.08.059 17098221 · DOI
- 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 Molecular and Cellular Biology 22 1172 1183 10.1128/MCB.22.4.1172-1183.2002 11809808 PMC134648 · DOI
- Jiang M Kang Y Sewastianik T Wang J Tanton H Alder K Dennis P Xin Y Wang Z Liu R Zhang M Huang Y Loda M Srivastava A Chen R Liu M Carrasco RD 2020 BCL9 provides multi-cellular communication properties in colorectal Cancer by interacting with paraspeckle proteins Nature Communications 11 7 10.1038/s41467-019-13842-7 PMC6946813 31911584 · DOI
- Kahn M 2014 Can we safely target the WNT pathway? Nature Reviews Drug Discovery 13 513 532 10.1038/nrd4233 24981364 PMC4426976 · DOI
- Kennedy MW Cha SW Tadjuidje E Andrews PG Heasman J Kao KR 2010 A co-dependent requirement of xBcl9 and Pygopus for embryonic body Axis development in Xenopus Developmental Dynamics 239 271 283 10.1002/dvdy.22133 19877304 · DOI
- Kim JJ Shajib MS Manocha MM Khan WI 2012 Investigating intestinal inflammation in DSS-induced model of IBD Journal of Visualized Experiments 1 3678 10.3791/3678 PMC3369627 22331082 · DOI
- Kramps T Peter O Brunner E Nellen D Froesch B Chatterjee S Murone M Züllig S Basler K 2002 Wnt/wingless signaling requires BCL9/legless-mediated recruitment of Pygopus to the nuclear beta-catenin-TCF complex Cell 109 47 60 10.1016/S0092-8674(02)00679-7 11955446 · DOI
- Li B Rhéaume C Teng A Bilanchone V Munguia JE Hu M Jessen S Piccolo S Waterman ML Dai X 2007 Developmental phenotypes and reduced wnt signaling in mice deficient for Pygopus 2 Genesis 45 318 325 10.1002/dvg.20299 17458864 · DOI
- Li D Sakuma R Vakili NA Mo R Puviindran V Deimling S Zhang X Hopyan S Hui CC 2014 Formation of proximal and anterior limb skeleton requires early function of Irx3 and Irx5 and is negatively regulated by shh signaling Developmental Cell 29 233 240 10.1016/j.devcel.2014.03.001 24726282 · DOI
- Lyou Y Habowski AN Chen GT Waterman ML 2017 Inhibition of nuclear wnt signalling: challenges of an elusive target for Cancer therapy British Journal of Pharmacology 174 4589 4599 10.1111/bph.13963 28752891 PMC5727325 · DOI
- Mani M Carrasco DE Zhang Y Takada K Gatt ME Dutta-Simmons J Ikeda H Diaz-Griffero F Pena-Cruz V Bertagnolli M Myeroff LL Markowitz SD Anderson KC Carrasco DR 2009 BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to Cancer cells Cancer Research 69 7577 7586 10.1158/0008-5472.CAN-09-0773 19738061 PMC4321734 · DOI
- Mieszczanek J van Tienen LM Ibrahim AEK Winton DJ Bienz M 2019 Bcl9 and pygo synergise downstream of apc to effect intestinal neoplasia in FAP mouse models Nature Communications 10 724 10.1038/s41467-018-08164-z 30760710 PMC6374407 · DOI
- Moor AE Anderle P Cantù C Rodriguez P Wiedemann N Baruthio F Deka J André S Valenta T Moor MB Győrffy B Barras D Delorenzi M Basler K Aguet M 2015 BCL9/9L-β-catenin signaling is associated with poor outcome in colorectal Cancer EBioMedicine 2 1932 1943 10.1016/j.ebiom.2015.10.030 26844272 PMC4703711 · DOI
- Mosimann C Hausmann G Basler K 2009 β-Catenin hits chromatin: regulation of wnt target gene activation Nature Reviews Molecular Cell Biology 10 276 286 10.1038/nrm2654 19305417 · DOI
- Mouradov D Sloggett C Jorissen RN Love CG Li S Burgess AW Arango D Strausberg RL Buchanan D Wormald S O'Connor L Wilding JL Bicknell D Tomlinson IP Bodmer WF Mariadason JM Sieber OM 2014 Colorectal Cancer cell lines are representative models of the main molecular subtypes of primary Cancer Cancer Research 74 3238 3247 10.1158/0008-5472.CAN-14-0013 24755471 · DOI · Paper page
- Nakamura Y de Paiva Alves E Veenstra GJC Hoppler S 2016 Tissue- and stage-specific wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules Development 143 1914 1925 10.1242/dev.131664 27068107 PMC4920159 · DOI
- Nusse R Clevers H 2017 Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities Cell 169 985 999 10.1016/j.cell.2017.05.016 28575679 · DOI · Paper page
- Parker DS Jemison J Cadigan KM 2002 Pygopus a nuclear PHD-finger protein required for Wingless signaling in Drosophila Development 129 2565 2576 10.3410/f.1006350.79562 12015286 · DOI
- Rouhi P Jensen LD Cao Z Hosaka K Länne T Wahlberg E Steffensen JF Cao Y 2010 Hypoxia-induced metastasis model in embryonic zebrafish Nature Protocols 5 1911 1918 10.1038/nprot.2010.150 21127485 · DOI
- Salazar VS Capelo LP Cantù C Zimmerli D Gosalia N Pregizer S Cox K Ohte S Feigenson M Gamer L Nyman JS Carey DJ Economides A Basler K Rosen V 2019 Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche eLife 8 e42386 10.7554/eLife.42386 30735122 PMC6386520 · DOI
- Schwab KR Patterson LT Hartman HA Song N Lang RA Lin X Potter SS 2007 Pygo1 and Pygo2 roles in wnt signaling in mammalian kidney development BMC Biology 5 15 10.1186/1741-7007-5-15 17425782 PMC1858683 · DOI
- Talla SB Brembeck FH 2016 The role of Pygo2 for wnt/ß-catenin signaling activity during intestinal tumor initiation and progression Oncotarget 7 80612 80632 10.18632/oncotarget.13016 27811361 PMC5348345 · DOI
- Valenta T Hausmann G Basler K 2012 The many faces and functions of β-catenin The EMBO Journal 31 2714 2736 10.1038/emboj.2012.150 22617422 PMC3380220 · DOI · Paper page
- van Tienen LM Mieszczanek J Fiedler M Rutherford TJ Bienz M 2017 Constitutive scaffolding of multiple wnt enhanceosome components by legless/BCL9 eLife 6 e20882 10.7554/eLife.20882 28296634 PMC5352222 · DOI
- Willmer T Cooper A Peres J Omar R Prince S 2017 The T-Box transcription factor 3 in development and Cancer BioScience Trends 11 254 266 10.5582/bst.2017.01043 28579578 · DOI · Paper page
- Zimmerli D Hausmann G Cantù C Basler K 2017 Pharmacological interventions in the wnt pathway: inhibition of wnt secretion versus disrupting the protein-protein interfaces of nuclear factors British Journal of Pharmacology 174 4600 4610 10.1111/bph.13864 28521071 PMC5727313 · DOI
- Authors
- Zimmerli, D., Borrelli, C., Jauregi-Miguel, A., Söderholm, S., Brütsch, S., Doumpas, N., Reichmuth, J., Murphy-Seiler, F., Aguet, M., Basler, K., Moor, A. E., & Cantù, C.
- Affiliations
- University of Zurich (CH)
- ETH Zurich (CH)
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden
- Linköping University (SE)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Basler, Konrad
- Moor, Andreas E
- Cantù, Claudio
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-08-18
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7434441
- OpenAlex
- W3056694453
- Cited by
- 47
- References
- 40
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 5 · 2023: 7 · 2022: 14 · 2021: 7 · 2020: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DiVA (Linkoping University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- Knut och Alice Wallenbergs Stiftelse
- Cancerfonden (CAN 2018/542)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PCEPP3_181249)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TBX3, BCL9, Wnt/β-catenin signaling, transcriptional coactivator, colorectal cancer, forelimb development, TCF/LEF, metastasis, tissue-specific gene regulation
- MeSH terms
- Animals, Female, Humans, Male, Organ Specificity, Transcription Factors, Tumor Cells, Cultured, Zebrafish, T-Box Domain Proteins, HCT116 Cells, Mice, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
