The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
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Abstract
Early during preimplantation development and in heterogeneous mouse embryonic stem cells (mESC) culture, pluripotent cells are specified towards either the primed epiblast or the primitive endoderm (PE) lineage. Canonical Wnt signaling is crucial for safeguarding naive pluripotency and embryo implantation, yet the role and relevance of canonical Wnt inhibition during early mammalian development remains unknown. Here, we demonstrate that transcriptional repression exerted by Wnt/TCF7L1 promotes PE differentiation of mESCs and in preimplantation inner cell mass. Time-series RNA sequencing and promoter occupancy data reveal that TCF7L1 binds and represses genes encoding essential naive pluripotency factors and indispensable regulators of the formative pluripotency program, including Otx2 and Lef1 . Consequently, TCF7L1 promotes pluripotency exit and suppresses epiblast lineage formation, thereby driving cells into PE specification. Conversely, TCF7L1 is required for PE specification as deletion of Tcf7l1 abrogates PE differentiation without restraining epiblast priming. Taken together, our study underscores the importance of transcriptional Wnt inhibition in regulating lineage specification in ESCs and preimplantation embryo development as well as identifies TCF7L1 as key regulator of this process.
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TCF7L1 and TBX3 are well-known repressors in development.
“TCF7L1 and TBX3 are indeed well-known repressors in development51,52”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [51]
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A Comparative Analysis of Extra-Embryonic Endoderm Cell Lines
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Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus
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“TCF7L1 peaks were called using GEM as described in De Jaime-Soguero et al., 2017.”
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Lluı́s, F., Ombrato, L., Pedone, E., Pepe, S., Merrill, B. J., & Cosma, M. P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017402108 · Cited by 54 · see citing works
Self-citationExpression of Wnt genes during mouse preimplantation development
Lloyd, S., Fleming, T. P., & Collins, J. E. (2003) · Gene Expression Patterns · doi:10.1016/s1567-133x(03)00046-2 · Cited by 52 · see citing works
Primitive endoderm differentiation: from specification to epithelium formation
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Leeneer, K. D., Hellemans, J., Steyaert, W., Lefever, S., Vereecke, I., Debals, E., Crombez, B., Baetens, M., Heetvelde, M. V., Coppieters, F., et al. (2014) · Human Mutation · doi:10.1002/humu.22739 · Cited by 46 · see citing works
Lackner, A., Sehlke, R., Garmhausen, M. R., Stirparo, G. G., Huth, M., Titz‐Teixeira, F., van der Lelij, P., Ramesmayer, J., Thomas, H., Ralser, M., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020105776 · Cited by 43 · see citing works
Convergence of cMyc and β‐catenin on Tcf7l1 enables endoderm specification
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Inhibition of β-catenin–TCF1 interaction delays differentiation of mouse embryonic stem cells
Chatterjee, S. S., Saj, A., Gocha, T., Murphy, M., Gonsalves, F. C., Zhang, X., Hayward, P. C., Oksuz, B. A., Shen, S. S., Madar, A., et al. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201503017 · Cited by 35 · see citing works
Aulicino, F., Pedone, E., Sottile, F., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.07.019 · Cited by 35 · see citing works
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Self-citationDeciphering liver zonation: New insights into the β-catenin, Tcf4, and HNF4α triad
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Embryonic stem cell identity grounded in the embryo
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Self-citationTcf7l1 directly regulates cardiomyocyte differentiation in embryonic stem cells
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TCF7L1 and TCF7 differentially regulate specific mouse ES cell genes in response to GSK-3 inhibitionPreprint
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Flagged first, then by citations
Research works printed but not linked: 1
- ten Berge, D. et al. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat. Cell Biol. 13, 1070–1075 (2011). · DOI
Cited by
Sorted by citations
Bravo González-Blas, C., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-023-01316-4 · Cited by 85 · see citing works
“TCF7L1 and TBX3 are indeed well-known repressors in development 51,52 and, while it has been previously reported that Tcf7l1 and Tbx3 expression is zonated in the adult mouse liver 43,53 , here we show their direct implication in liver zonation regulation by enhancer-GRN mapping.”
Jung, J. P., Olutoye, O. O., Prajapati, T. J., et al. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.04.047 · Cited by 18 · see citing works
Plakoglobin is a mechanoresponsive regulator of naive pluripotency
Meglio, I. D., Jonghe, J. D., Ellermann, A. L., Yanagida, A., Herger, M., Slatery, E. M., Weberling, A., Munger, C., Fischer, K., Mulas, C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39515-0 · Cited by 15 · see citing works
Engineered hematopoietic and immune cells derived from human pluripotent stem cells
Chang, Y., Hummel, S. N., Jung, J., Jin, G., Deng, Q., & Bao, X. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.08.006 · Cited by 11 · see citing works
Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts
Wong, K. W., Zeng, Y., Tay, E., Teo, J. H. J., Cipta, N. O., Hamashima, K., Yi, Y., Liu, H., Warrier, T., Le, M. T. N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54381-0 · Cited by 10 · see citing works
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“XEN cells were obtained following a protocol by Niakan et al. with minor changes [36].”
Persistent Wnt signaling affects IVF embryo implantation and offspring metabolism
Jia, Y., Liu, Y., Li, Y., Guan, X., Xu, J., Yan, Z., Liu, K., Zhang, Y., Bai, D., Xiang, J., et al. (2025) · 中国科学通报：英文版 · doi:10.1016/j.scib.2025.05.003 · Cited by 7 · see citing works
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SRRM2 splicing factor modulates cell fate in early development
Carvalho, S., Zea-Redondo, L., Tang, T. C. C., Stachel-Braum, P., Miller, D. C., Caldas, P., Kukalev, A., Diecke, S., Grosswendt, S., Grosso, A. R., et al. (2024) · Biology Open · doi:10.1242/bio.060415 · Cited by 6 · see citing works
Perera, M., & Brickman, J. M. (2024) · Development · doi:10.1242/dev.202842 · Cited by 5 · see citing works
Regulatory role of miRNAs in Wnt signaling pathway linked with cardiovascular diseases
Behera, J. K., Bhattacharya, M., Mishra, P. K., Mishra, A., Dash, A. A., Kar, N. B., Behera, B., & Patra, B. C. (2022) · Current Research in Pharmacology and Drug Discovery · doi:10.1016/j.crphar.2022.100133 · Cited by 6 · see citing works
“Conversely deletion of TCF7L1 protein led to cardiomyocyte formation as the study was carried out on themouse model (Athanasouli and Balli, 2022).”
MethodEnhancer grammar of liver cell types and hepatocyte zonation states
González-Blas, C. B., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2022) · doi:10.1101/2022.12.08.519575 · Cited by 5 · see citing works
Divergent destinies: insights into the molecular mechanisms underlying EPI and PE fate determination
Athanasouli, P., Vanhessche, T., & Lluı́s, F. (2025) · Life Science Alliance · doi:10.26508/lsa.202403091 · Cited by 5 · see citing works
Self-citationRoss, C., Balestrini, P. A., Bates, L. E., Azami, T., Adakole, T., Semple, M. J., Salonna, M., Gyuris, R., Nichols, J., Fogarty, N. E., et al. (2025) · Journal of Cell Science · doi:10.1242/jcs.264257 · Cited by 5 · see citing works
Fernkorn, M., & Schröter, C. J. (2025) · Journal of Cell Science · doi:10.1242/jcs.263794 · Cited by 5 · see citing works
Duan, J., Zhou, X., Zhu, H., Zhou, M., Liu, M., Zhou, Y., Li, W., Xu, B., & Zhang, A. (2025) · Molecular Medicine · doi:10.1186/s10020-024-01054-9 · Cited by 4 · see citing works
“It is closely associated with cell proliferation, stem cell expansion, regeneration, and tumorigenesis and plays important roles in embryonic development and tissue homeostasis maintenance (Beh-rens et al. 1996; Athanasouli et al. 2023).”
Wnt/β-catenin signalling modulates the timing of cell fate decision making in the early mouse embryo
Lilao‐Garzón, J., Corujo-Simón, E., Vinyoles, M., Fischer, S., Guillén, J. Á., Balayo, T., & Descalzo, S. M. (2026) · PLoS ONE · doi:10.1371/journal.pone.0344295 · Cited by 3 · see citing works
“Another study points towards activation of the pathway leading to Epi fate [39].”
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Expression of Wnt signaling proteins in rare congenital bladder disorders
Xie, B., Millar, M., Arthurs, C., et al. (2024) · Journal of Pediatric Urology · doi:10.1016/j.jpurol.2024.09.029 · Cited by 3 · see citing works
“…[15]; Connexin 43 (Cx43) [16], a protein proposed to translocate into the nucleus with b -catenin after Wnt signal activation; FRA1 [17] and TCF7L1 [18], Wnt targeted downstream transcription factors in BE, NGB and PUV tissue using an unbiased, semi-automated quantitative immunohistochemical…”
Shi, H., Ge, Q., Pan, M., Sheng, Y., Qi, T., Zhou, Y., Sun, Y., Bai, Y., & Cai, L. (2024) · Analytica Chimica Acta · doi:10.1016/j.aca.2024.342331 · Cited by 2 · see citing works
Jiao, Y., Liu, J., Li, C., Hu, Y., & Zhao, S. (2025) · Journal of Developmental Biology · doi:10.3390/jdb13030033 · Cited by 2 · see citing works
“In mouse embryos derived from IVF, the inhibition of the Wnt pathway has been reported to promote the formation of the PrE, thereby promoting embryonic development [57].”
Matsubara, K., Hirota, M., Kajiwara, K., Senga, H., Matsui, S., Marutani, M., & Seki, Y. (2025) · Development · doi:10.1242/dev.204886 · Cited by 1 · see citing works
Metastatic Osteosarcoma is Characterized by Loss of Osteoblastic Lineage FidelityPreprint
Tanaka, Y., Morrow, J. J., Casaní-Galdón, S., Pimenta, E. M., Li, J., Butaney, B., Farran, C. A. E., Karam, J., D’Antonio, J. P., Bi, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.10.731352 · Cited by 1 · see citing works
Themistoklis, K., & Nikolaou, C. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-31978-5_21
Self-citationPerera, M., & Brickman, J. (2024) · bioRxiv · doi:10.1101/2024.02.29.582771
“In naïve ESCs, canonical ß-catenin signalling exploits TCF3 to support pluripotency, by associating with these regulatory regions and counteracting TCF3-mediated repression(Athanasouli et al., 2023; Watanabe and Dai, 2011).”
BackgroundLi, Z., Huang, Y., Ha, S., Wang, X., Pang, Y., Huang, J., Liu, L., Ru, G., & Peng, S. (2025) · Research Square · doi:10.21203/rs.3.rs-6242185/v1
Lee, Y., & Tae, J. (2025) · International Journal of Stem Cells · doi:10.15283/ijsc25078
“Wnt/ β -catenin signaling also contributes; its inhibition reduces EPI specification while promoting PrE fate (74).”
Shi, H., Sheng, Y., Zhang, C., et al. (2026) · The FASEB Journal · doi:10.1096/fj.202504288rr
“At the same time, a large number of new mRNA and proteins were synthesized [44], which was consistent with this study.”
Kwon, J., Zhang, J. Y., Shy, B. R., et al. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2026.102980
Identification and characterization of POSTN+ synovial progenitor cells in meniscus regeneration
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- Authors
- Athanasouli, P., Balli, M., De Jaime-Soguero, A., Boel, A., Papanikolaou, S., van der Veer, B. K., Janiszewski, A., Vanhessche, T., Francis, A., El Laithy, Y., Nigro, A. L., Aulicino, F., Koh, K. P., Pasque, V., Cosma, M. P., Verfaillie, C., Zwijsen, A., Heindryckx, B., Nikolaou, C., & Lluis, F.
- Affiliations
- Leuven Stem Cell Institute (BE)
- Ghent University Hospital (BE)
- University of Crete (GR)
- KU Leuven (BE)
- Centre for Genomic Regulation (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- ORCID
- Venue
- Nature Communications
- Published
- 2023-03-03
- Volume
- 14
- Issue
- 1
- Pages
- 1210-1210
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9984534
- OpenAlex
- W4323046045
- Semantic Scholar
- c3291116d1d783c22ecb4b2f4ffba55290aae7b8
- Cited by
- 31
- References
- 112
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 8 · 2023: 3 · 2022: 2
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fonds Wetenschappelijk Onderzoek (11M7822N, 11E7920N, G073622N, G097618N, G091521N)
- Katholieke Universiteit Leuven | Universitaire Ziekenhuizen Leuven, KU Leuven (PDM/18/212, C14/21/115)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Wnt signaling, TCF7L1, primitive endoderm, naive pluripotency, transcriptional repression, Otx2, LEF1, preimplantation embryo, inner cell mass, mouse embryonic stem cells, lineage specification, Wnt signaling inhibition
- MeSH terms
- Animals, Automobile Driving, Blastocyst, Cell Differentiation, Endoderm, Female, Germ Layers, Pregnancy, Mice, Transcription Factor 7-Like 1 Protein
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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.
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