TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme
Open accessAbstract
The organized array of smooth muscle cells (SMCs) and fibroblasts in the walls of visceral tubular organs arises by patterning and differentiation of mesenchymal progenitors surrounding the epithelial lumen. Here, we show that the TBX2 and TBX3 transcription factors have novel and required roles in regulating these processes in the murine ureter. Co-expression of TBX2 and TBX3 in the inner mesenchymal region of the developing ureter requires canonical WNT signaling. Loss of TBX2/TBX3 in this region disrupts activity of two crucial drivers of the SMC program, Foxf1 and BMP4 signaling, resulting in decreased SMC differentiation and increased extracellular matrix. Transcriptional profiling and chromatin immunoprecipitation experiments revealed that TBX2/TBX3 directly repress expression of the WNT antagonists Dkk2 and Shisa2, the BMP antagonist Bmper and the chemokine Cxcl12. These findings suggest that TBX2/TBX3 are effectors of canonical WNT signaling in the ureteric mesenchyme that promote SMC differentiation by maintaining BMP4 and WNT signaling in the inner region, while restricting CXCL12 signaling to the outer layer of fibroblast-fated mesenchyme.
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TBX3 and TBX2 are closely entangled in other regulatory programs, such as Wnt and Hedgehog signaling, and both are essential for proper limb, lung, and ureter development.
“TBX3 and TBX2 are closely entangled in other regulatory programs, such as Wnt and Hedgehog signaling, and both are essential for proper limb [8], lung [9], and ureter development [10].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [10]
The paper’s title states that TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme. Citation [10] is attached to ureter development, but the available passages do not establish the stronger claim that each gene is essential for proper ureter development. The limb and lung claims have separate citations. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTbx3 interacts with certain parts of the Wnt and Hedgehog signaling pathways.
“Interestingly, Tbx3 interacts with certain parts of the Wnt and Hedgehog signaling pathways [8–10].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [10]
The paper title in our indexed copy identifies TBX3 as acting downstream of canonical WNT signaling in mouse ureteric mesenchyme, supporting the WNT part of the claim. The available passages contain no discussion of Hedgehog signaling, so they do not support that part (searched: Hedgehog, SHH, and TBX3). No page numbers are available for these passages. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTbx3 is a target of Wnt signaling in the liver.
“We verified that Tbx3 is a target of Wnt signaling in the liver, by either over-activating or eliminating the Wnt pathway in the tissue (Figure .1A, arrows point to TBX3 + Apc KO cells, arrowheads point to TBX3 -Wls KO cells), in agreement with data from other contexts”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Aydoğdu et al. 2018
The title in our copy identifies TBX3 as acting downstream of canonical WNT signaling in mouse ureteric mesenchyme, supporting the citing sentence’s reference to data from another context. It does not establish that TBX3 is a WNT target in the liver; the liver experiments are presented as the citing authors’ own work. (LLM, conf=0.79)
Experimental — accuracy not yet measuredTbx3 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 [27]
Redundancy between Tbx3 and Tbx2 to compensate for each other has been reported in several organs.
“Interestingly, redundancy between Tbx3 and Tbx2 to compensate for each other has been reported in several organs [9, 10].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [10]
The available copy contains bibliographic metadata and a link to the paper, but no passage discussing functional redundancy or compensation between Tbx2 and Tbx3 in any organ. Searches for “redundancy” and “redundant” did not locate evidence for the claim. (LLM, conf=0.70)
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References 71 · Cited by 41
- Authors
- Aydoğdu, N., Rudat, C., Trowe, M.-O., Kaiser, M., Lüdtke, T. H., Taketo, M. M., Christoffels, V. M., Moon, A., & Kispert, A.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Kyoto University (JP)
- Amsterdam UMC Location University of Amsterdam (NL)
- Geisinger Medical Center (US)
- Corresponding author
- Kispert, Andreas
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2018-11-26
- Volume
- 145
- Issue
- 23
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2902459693
- Cited by
- 41
- References
- 71
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 2 · 2019: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Renal and related cancers
- 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
- TBX2, TBX3, Wnt/β-catenin signaling, smooth muscle differentiation, fibroblast differentiation, FOXF1, BMP4, extracellular matrix, DKK2, BMPER, CXCL12, transcriptional repression, ureter development
- MeSH terms
- Animals, Cell Differentiation, Embryo, Mammalian, Mesoderm, Models, Biological, Peristalsis, Ureter, Gene Expression Regulation, Developmental, Body Patterning, T-Box Domain Proteins, Myocytes, Smooth Muscle, Mice, Bone Morphogenetic Protein 4, Transcriptome, Wnt Signaling Pathway
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