Embryonic Tbx3+ cardiomyocytes form the mature cardiac conduction system by progressive fate restriction
Open accessAbstract
A small network of spontaneously active Tbx3+ cardiomyocytes forms the cardiac conduction system (CCS) in adults. Understanding the origin and mechanism of development of the CCS network are important steps towards disease modeling and the development of biological pacemakers to treat arrhythmias. We found that Tbx3 expression in the embryonic mouse heart is associated with automaticity. Genetic inducible fate mapping revealed that Tbx3+ cells in the early heart tube are fated to form the definitive CCS components, except the Purkinje fiber network. At mid-fetal stages, contribution of Tbx3+ cells was restricted to the definitive CCS. We identified a Tbx3+ population in the outflow tract of the early heart tube that formed the atrioventricular bundle. Whereas Tbx3+ cardiomyocytes also contributed to the adjacent Gja5+ atrial and ventricular chamber myocardium, embryonic Gja5+ chamber cardiomyocytes did not contribute to the Tbx3+ sinus node or to atrioventricular ring bundles. In conclusion, the CCS is established by progressive fate restriction of a Tbx3+ cell population in the early developing heart, which implicates Tbx3 as a useful tool for developing strategies to study and treat CCS diseases.
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The Tbx3-Venus reporter system is validated.
“To visualize the activity of the murine Tbx3 promoter at the protein level, we used a validated Tbx3-Venus (Tbx3tm1(Venus)Vmc) [11, 42–47] reporter system (Fig. 2a).”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [45]
The supplied passages and indexed results show bibliographic information, not a description or validation of the reporter system. Searches for Tbx3-Venus, the allele designation, and Venus reporter validation found no passage addressing the claim in our copy. (LLM, conf=0.72)
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The roles and regulation of TBX3 in development and disease
Khan, S. F., Damerell, V., Omar, R., Du Toit, M., Khan, M., Maranyane, H. M., Mlaza, M., Bleloch, J., Bellis, C., Sahm, B. D. B., et al. (2020) · Gene · doi:10.1016/j.gene.2019.144223 · Cited by 99 · see citing works
“Lineage tracing showed that the SAN originates from Tbx3 positive cells in the early heart tube (Mohan et al., 2018).”
BackgroundTranscriptome analysis of mouse and human sinoatrial node cells reveals a conserved genetic program
van Eif, V., Stefanovic, S., van Duijvenboden, K., Bakker, M., Wakker, V., de Gier-de Vries, C., Zaffran, S., Verkerk, A. O., Boukens, B. J., & Christoffels, V. (2019) · Development · doi:10.1242/dev.173161 · Cited by 76 · see citing works
Self-citationMohan, R. A., Bosada, F. M., van Weerd, J. H., van Duijvenboden, K., Wang, J., Mommersteeg, M. T. M., Hooijkaas, I. B., Wakker, V., de Gier-de Vries, C., Coronel, R., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1919379117 · Cited by 39 · see citing works
Self-citationTBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration
Melzer, M. K., Schirge, S., Gout, J., Arnold, F., Srinivasan, D., Burtscher, I., Allgöwer, C., Mulaw, M., Zengerling, F., Günes, C., et al. (2023) · BMC Biology · doi:10.1186/s12915-023-01553-x · Cited by 5 · see citing works
“In this model, the production of Venus protein reflects Tbx3 promoter activity as detected with anti-GFP antibodies [42, 45].”
BackgroundSelf-citation
- Authors
- Mohan, R. A., Mommersteeg, M. T. M., Domínguez, J. N., Choquet, C., Wakker, V., de Gier-de Vries, C., Boink, G. J. J., Boukens, B. J., Miquerol, L., Verkerk, A. O., & Christoffels, V. M.
- Affiliations
- Amsterdam University Medical Centers (NL)
- University of Oxford (GB)
- University of Jaén 4 Department of Experimental Biology , , Jaén 23071 , Spain
- Centre National de la Recherche Scientifique (FR)
- Amsterdam University Medical Centers, University of Amsterdam 1 Department of Medical Biology , , Amsterdam 1105 AZ , The Netherlands
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2018-09-01
- Volume
- 145
- Issue
- 17
- Pages
- dev167361
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2884014832
- Cited by
- 50
- References
- 0
- Citations by year
- 2026: 10 · 2025: 3 · 2024: 10 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 1
- FWCI
- 2.04
- 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)
- HAL AMU (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Hartstichting (2010B205, 2014T065, 2016T047)
- Fondation Leducq
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ZonMw Veni 016.156.162)
- European Research Council (714866)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TBX3, cardiac conduction system, embryonic heart development, automaticity, His bundle, sinoatrial node, Purkinje fibers, connexin 40, heart tube, fate mapping, biological pacemaker, cardiac arrhythmias
- MeSH terms
- Gap Junction alpha-5 Protein, Animals, Bundle of His, Male, Mice, Inbred C57BL, Mice, Transgenic, Connexins, Gene Expression Regulation, Developmental, T-Box Domain Proteins, Myocytes, Cardiac, Organogenesis, Embryo Culture Techniques, Mice
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