Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria
Open accessAbstract
The sinoatrial node initiates the heartbeat and controls the rate and rhythm of contraction, thus serving as the pacemaker of the heart. Despite the crucial role of the sinoatrial node in heart function, the mechanisms that underlie its specification and formation are not known. Tbx3, a transcriptional repressor required for development of vertebrates, is expressed in the developing conduction system. Here we show that Tbx3 expression delineates the sinoatrial node region, which runs a gene expression program that is distinct from that of the bordering atrial cells. We found lineage segregation of Tbx3-negative atrial and Tbx3-positive sinoatrial node precursor cells as soon as cardiac cells turn on the atrial gene expression program. Tbx3 deficiency resulted in expansion of expression of the atrial gene program into the sinoatrial node domain, and partial loss of sinoatrial node-specific gene expression. Ectopic expression of Tbx3 in mice revealed that Tbx3 represses the atrial phenotype and imposes the pacemaker phenotype on the atria. The mice displayed arrhythmias and developed functional ectopic pacemakers. These data identify a Tbx3-dependent pathway for the specification and formation of the sinoatrial node, and show that Tbx3 regulates the pacemaker gene expression program and phenotype.
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TBX3 antibody specificity was confirmed using a global Tbx3 knockout.
“By using a global knockout of Tbx3 through the replacement of the first three exons by a Cre-knockin [48], we confirmed TBX3 antibody specificity (Additional file 1: Fig. S3a).”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [48]
The cited paper’s Materials and methods describes a Cre knock-in that produced a Tbx3 null allele, supporting the identification of a Tbx3 knockout. But it says the first three codons in the first exon—not the first three exons—were replaced. The antibody-specificity confirmation is presented as the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.88)
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References 60 · Cited by 409
Research works printed but not linked: 6
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- Stieber, J., Herrmann, S., Feil, S., Loster, J., Feil, R., Biel, M., Hofmann, F., and Ludwig, A. 2003. The hyperpolarization- activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc. Natl. Acad. Sci. 100: 15235-15240.
- Authors
- Hoogaars, W. M. H., Engel, A., Brons, J. F., Verkerk, A. O., de Lange, F. J., Wong, L. Y. E., Bakker, M. L., Clout, D. E., Wakker, V., Barnett, P., Ravesloot, J. H., Moorman, A. F. M., Verheijck, E. E., & Christoffels, V. M.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-05-01
- Volume
- 21
- Issue
- 9
- Pages
- 1098-1112
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1855235
- OpenAlex
- W2168881898
- Cited by
- 409
- References
- 60
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 24 · 2023: 19 · 2022: 17 · 2021: 24 · 2020: 27 · 2019: 19 · 2018: 25 · 2017: 16 · 2016: 18 · 2015: 27 · 2014: 21 · 2013: 22 · 2012: 34
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (864-05-006, 912-03-043)
- 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, sinoatrial node, cardiac pacemaker, transcriptional repression, cardiac conduction system, lineage segregation, ectopic pacemaker, cardiac arrhythmias, heart development
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Heart Atria, Mice, Transgenic, Sinoatrial Node, Atrial Function, DNA Primers, Mice, Knockout, Gene Expression Regulation, Developmental, T-Box Domain Proteins, Myoblasts, Cardiac, Mice
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