Reptilian heart development and the molecular basis of cardiac chamber evolution
Open accessAbstract
The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution.
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tbx5 expression is confined to the left ventricle in developing amniote heart but across the common ventricle in the three-chambered reptile heart.
“Expression of this gene is confined to the left ventricle in the developing amniote heart but is expressed across the common ventricle in the three chambered reptile heart (Koshiba-Takeuchi et al., 2009).”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Koshiba-Takeuchi et al., 2009
The Abstract reports that Tbx5 is enriched in the prospective left ventricle of birds and mammals, but describes a gradient rather than expression confined to that ventricle. It also reports expression throughout the anole ventricle, while turtle expression becomes left-enriched at later stages. The claim therefore overgeneralizes both the amniote and reptile patterns. (LLM, conf=0.87)
Experimental — accuracy not yet measuredtbx5 is regulated differently during heart formation in reptiles than in birds and mammals, a Class-level difference.
“the tbx5 gene, deeply embedded in the vertebrate heart formation GRN (for review Davidson, 2006), turns out to be regulated differently during heart formation in reptiles than in birds and mammals, a Class-level difference.”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Koshiba-Takeuchi et al., 2009
The passage on ventricular patterning (page unavailable) reports broad early Tbx5 expression in turtle and anole hearts, unlike the early restriction in chick and mouse. But it also reports a later left–right gradient in turtles and distinguishes avian/crocodilian hearts from the reptilian hearts studied. The evidence supports a difference in developmental expression patterns, not a uniform difference across the entire reptile class. (LLM, conf=0.84)
Experimental — accuracy not yet measuredForcing uniform tbx5 expression in mouse heart or preventing left ventricle tbx5 expression produced a three-chambered heart lacking an interventricular septum.
“When uniform tbx5 expression was forced in the mouse heart, or left ventricle tbx5 expression was prevented, i.e., if a reptilian tbx5 spatial regulatory expression was imposed, the mouse developed a three-chambered heart lacking an interventricular septum.”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Koshiba-Takeuchi et al., 2009
The paper reports that broad Tbx5 misexpression in mouse ventricles produced a single ventricle or defective septation, and that ventricular Tbx5 deletion produced a single mispatterned ventricle (passages 1–2, Abstract; pages unavailable). It does not describe a specifically left-ventricle-targeted deletion: the septation experiment in passage 3 deletes Tbx5 in right-ventricle and septum precursors while sparing the left-ventricular free wall. Some misexpression embryos also retained a rudiment of a septum, so an absent septum was not universal. (LLM, conf=0.86)
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- Authors
- Koshiba-Takeuchi, K., Mori, A. D., Kaynak, B. L., Cebra-Thomas, J., Sukonnik, T., Georges, R. O., Latham, S., Beck, L., Henkelman, R. M., Black, B. L., Olson, E. N., Wade, J., Takeuchi, J. K., Nemer, M., Gilbert, S. F., & Bruneau, B. G.
- Affiliations
- Gladstone Institutes (US)
- Montreal Clinical Research Institute (CA)
- Michigan State University (US)
- University of Toronto (CA)
- University of California, San Francisco (US)
- The University of Texas Southwestern Medical Center (US)
- Tokyo Institute of Technology (JP)
- University of Ottawa (CA)
- Swarthmore College (US)
- Corresponding author
- Bruneau, Benoit G.
- ORCID
- Venue
- Nature
- Published
- 2009-09-03
- Volume
- 461
- Issue
- 7260
- Pages
- 95-98
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2753965
- OpenAlex
- W2025218263
- Cited by
- 182
- References
- 29
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 31 · 2023: 5 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 11 · 2018: 10 · 2017: 13 · 2016: 9 · 2015: 7 · 2014: 12 · 2013: 10 · 2012: 11
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-09-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Works - Scholarship, Research, & Creative Expression (Swarthmore College) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Heart, Lung, and Blood Institute (P01HL089707, R01HL064658)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- cardiac septation, TBX5, Anolis carolinensis, red-eared slider turtle, red-eared slider, left ventricle, endothermy evolution
- MeSH terms
- Animals, Chick Embryo, Heart, Lizards, Turtles, Gene Expression Regulation, Developmental, Evolution, Molecular, T-Box Domain Proteins, Organogenesis, Mice
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