Reptilian heart development and the molecular basis of cardiac chamber evolution

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.

• Publication year

  2009

• Venue

  Nature

• Publication date

  2009-08-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature08324PMID 19727199PMCID 2753965
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Turtles all the way down: loggerheads at the root of the chelonian tree

  2009cited by this paper
• A developmental staging series for the lizard genus Anolis: A new system for the integration of evolution, development, and ecology

  2008cited by this paper
• Evo‐Devo and an Expanding Evolutionary Synthesis

  2008cited by this paper
• The developmental genetics of congenital heart disease

  2008cited by this paper
• Molecular cloning of natriuretic peptides from the heart of reptiles: loss of ANP in diapsid reptiles and birds.

  2008cited by this paper
• Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

  2008cited by this paper
• Phylogenomics of nonavian reptiles and the structure of the ancestral amniote genome

  2007cited by this paper
• Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart

  2006cited by this paper
• Gene Regulatory Networks in the Evolution and Development of the Heart

  2006cited by this paper
• Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis.

  2006cited by this paper
• T-box transcription factors and their roles in regulatory hierarchies in the developing heart

  2005cited by this paper
• The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field.

  2005cited by this paper
• Evidence for Endothermic Ancestors of Crocodiles at the Stem of Archosaur Evolution

  2004cited by this paper
• The Evolution of Endothermy in Terrestrial Vertebrates: Who? When? Why?

  2004cited by this paper
• Baf60c is essential for function of BAF chromatin remodelling complexes in heart development

  2004cited by this paper
• The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner

  2004cited by this paper
• BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

  2004cited by this paper
• Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis

  2003cited by this paper
• Staging criteria for embryos of the spiny softshell turtle, Apalone spinifera (testudines: Trionychidae)

  2002cited by this paper
• The physiological and evolutionary significance of cardiovascular shunting patterns in reptiles.

  2002cited by this paper
• A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.

  2001cited by this paper
• Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome.

  1999cited by this paper
• Turtle Origins

  1999cited by this paper
• Evolution of the vertebrate cardio-pulmonary system.

  1999cited by this paper
• A molecular phylogeny of reptiles.

  1999cited by this paper
• Tbx5 is essential for heart development.

  1999cited by this paper
• Biology of the Reptilia

  1984cited by this paper
• Comparative cardiac anatomy of the reptilia. III. The heart of crocodilians and an hypothesis on the completion of the interventricular septum of crocodilians and birds

  1979cited by this paper
• A reconsideration of the phylogeny of the tetrapod heart

  1975cited by this paper
• Biology of the Reptilia

  1969cited by this paper
• Evidence for Endothermic Ancestors of Crocodiles at the Stem of Archosaur Evolution

  year unknowncited by this paper
• Beiträge zur vergleichenden Anatomie und Entwicklungsgeschichte der Wirbelthiere.

  year unknowncited by this paper

• Trunk Muscle Differentiation and Growth in Vertebrates.

  2026cites this paper
• The Interplay of Ontogeny and Phylogeny at the Transcriptome Level of the Tetrapod Heart

  2025cites this paper
• Single-nuclei multiomics analysis identifies abnormal cardiomyocytes in a murine model of cardiac development

  2025cites this paper
• Lizard anesthesia-a retrospective study of anesthetic protocol and monitoring quality of anesthetic episodes at a veterinary hospital over 23 years (2000-2023).

  2025cites this paper
• Comparative genomics sheds light on mammalian and avian gene regulation and phenotypic evolution

  2025influential citation
• Developmental and Evolutionary Heart Adaptations Through Structure–Function Relationships

  2025cites this paper
• A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects

  2025cites this paper
• Regulation of atrial and ventricular cardiomyocyte identity.

  2025cites this paper
• A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects

  2024cites this paper
• On the involvement of the second heart field in congenital heart defects.

  2024cites this paper
• Embryonic development and transcriptomic analysis in red-eared slider Trachemys scripta elegans under salinity stress.

  2024cites this paper
• The Biology of Us

  2024cites this paper
• Ventricular Septal Defects: Molecular Pathways and Animal Models.

  2024cites this paper
• Molecular regulation of reversible cardiac remodeling: lessons from species with extreme physiological adaptations.

  2024cites this paper
• Comparison of reconstruction methods for optical projection tomography with sparse angle projections

  2024cites this paper
• The molecular mechanisms of cardiac development and related diseases

  2024cites this paper
• Single-cell morphometrics reveals T-box gene-dependent patterns of epithelial tension in the Second Heart field

  2024cites this paper
• Evolutionary Aspects of Chamber Formation and Septation.

  2024cites this paper
• Genetics and etiology of congenital heart disease.

  2024cites this paper
• Sur l’implication du second champ cardiaque dans les malformations cardiaques congénitales

  2024cites this paper
• The heart field transcriptional landscape at single-cell resolution.

  2023cites this paper
• Developmental heart morphology in the Amazon turtle Podocnemis expansa (Testudines: Podocnemidae)

  2023cites this paper
• Narrative review of single ventricle: where are we after 40 years?

  2023cites this paper
• Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

  2023cites this paper
• Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy

  2023cites this paper
• The cloning era and the cloning of Brachury and other T/t complex genes

  2022cites this paper
• Single ventricle: amphibians and human beings

  2022cites this paper
• Heart morphology during the embryonic development of Podocnemis unifilis Trosquel 1948 (Testudines: Podocnemididae)

  2022cites this paper
• Comparative and Functional Anatomy of the Ectothermic Sauropsid Heart.

  2022cites this paper
• Anguimorpha as a model group for studying the comparative heart morphology among Lepidosauria: Evolutionary window on the ventricular septation

  2022cites this paper
• SIRT methods for the iterative solution of sparse OPT data reconstruction

  2022cites this paper
• Embryology of the Heart

  2021cites this paper
• Genetic analysis of right heart structure and function in 40,000 people

  2021cites this paper
• A comparative analysis of heart microRNAs in vertebrates brings novel insights into the evolution of genetic regulatory networks

  2021cites this paper
• Persistent Ventricle Partitioning in the Adult Zebrafish Heart

  2021influential citation
• Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of TRIM72 in Primates

  2021cites this paper
• Genetic determinants of interventricular septal anatomy and the risk of ventricular septal defects and hypertrophic cardiomyopathy

  2021cites this paper
• Cardiac Development: A Glimpse on Its Translational Contributions

  2021cites this paper
• Heart Development and Congenital Structural Heart Defects.

  2021cites this paper
• Advancing human disease research with fish evolutionary mutant models.

  2021cites this paper
• Cardiac Structures in Marine Animals Provide Insight on Potential Directions for Interventions for Pediatric Congenital Heart Defects.

  2021cites this paper
• The formation of the atrioventricular conduction axis is linked in development to ventricular septation

  2020cites this paper
• In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix

  2020cites this paper
• The lateral plate mesoderm

  2020cites this paper
• Cardiac natriuretic peptides

  2020cites this paper
• Cholecystokinin peptide signaling is regulated by a TBX5-MEF2 axis in the heart.

  2020cites this paper
• The development of the trunk neural crest in the turtle Trachemys scripta

  2020cites this paper
• A systematic study of injectable anesthetic agents in the brown anole lizard (Anolis sagrei )

  2020cites this paper
• Vitamin A as a Transcriptional Regulator of Cardiovascular Disease

  2020cites this paper
• Identification of the building blocks of ventricular septation in monitor lizards (Varanidae)

  2019cites this paper
• Reptiles as a Model System to Study Heart Development.

  2019influential citation
• Up-Down and Left-Right by the Heart Transcriptome

  2019cites this paper
• MORFOLOGIA E EVOLUÇÃO DO CORAÇÃO NOS VERTEBRADOS: UMA REVISÃO

  2019cites this paper
• Commemoration of Comparative Cardiac Anatomy of the Reptilia I‐IV

  2019cites this paper
• Heart development in the lizards (Varanidae) with the greatest extent of ventricular septation

  2019cites this paper
• Krogh’s Principle and Why the Modern Zoo Is Important to Academic Research

  2019cites this paper
• Retinoic acid signaling in heart development

  2019cites this paper
• Development and evolution of the metazoan heart

  2019cites this paper
• Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease

  2019cites this paper
• Regulation and evolution of muscle development in tunicates

  2019cites this paper
• Identification of satellite cells from anole lizard skeletal muscle and demonstration of expanded musculoskeletal potential.

  2018cites this paper
• HNK‐1 in Morphological Study of Development of the Cardiac Conduction System in Selected Groups of Sauropsida

  2018cites this paper
• Turtle spongious ventricles exhibit more compliant diastolic property and possess larger elastic regions of connectin in comparison to rat compact left ventricles

  2018cites this paper
• Characterisation of cardiomyocyte plasticity and the role of fibroblasts during zebrafish heart regeneration

  2018influential citation
• Evolutionarily conserved Tbx5–Wnt2/2b pathway orchestrates cardiopulmonary development

  2018cites this paper
• Molecular and Cellular Biology of the Right Heart

  2018cites this paper
• Embryological Origins: How Does the Right Ventricle Form

  2018cites this paper
• Cardiac septation in heart development and evolution

  2018cites this paper
• Important cardiac transcription factor genes are accompanied by bidirectional long non-coding RNAs

  2018cites this paper
• into the evolutionary loss of limbs in snakes

  2018cites this paper
• Distinct myocardial lineages break atrial symmetry during cardiogenesis in zebrafish

  2018influential citation
• Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration

  2018cites this paper
• Does Fractal Analysis of the Right Side of the Heart Provide Insight into Pulmonary Hypertension?

  2018cites this paper
• Precardiac organoids form two heart fields via Bmp/Wnt signaling

  2018cites this paper
• Developmental, genetic, and genomic insights into the evolutionary loss of limbs in snakes

  2018cites this paper
• Deep Homology?: Uncanny Similarities of Humans and Flies Uncovered by Evo-Devo

  2017cites this paper
• On the Evolution of the Cardiac Pacemaker

  2017cites this paper
• KLF13 is a genetic modifier of the Holt‐Oram syndrome gene TBX5

  2017cites this paper
• The HAND1 frameshift A126FS mutation does not cause hypoplastic left heart syndrome in mice

  2017cites this paper
• The concept of macroevolution in view of modern data

  2017cites this paper
• Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function

  2017cites this paper
• The vertebrate heart: an evolutionary perspective

  2017cites this paper
• Model Clades Versus Model Species: Anolis Lizards as an Integrative Model of Anatomical Evolution.

  2017cites this paper
• TBX5: A Key Regulator of Heart Development.

  2017influential citation
• Early frameshift alleles of zebrafish tbx5a that fail to develop the heartstrings phenotype

  2017cites this paper
• Sequential segmental analysis of the crocodilian heart

  2017cites this paper
• Evolution, comparative biology and ontogeny of vertebrate heart regeneration

  2016cites this paper
• Evolution of Dosage Compensation in Anolis carolinensis, a Reptile with XX/XY Chromosomal Sex Determination

  2016cites this paper
• Functional Analysis of KLF13 in the Heart

  2016cites this paper
• Combinatorial Functions of Transcription Factors and Epigenetic Factors in Heart Development and Disease

  2016cites this paper
• Convergent evolutionary reduction of atrial septation in lungless salamanders

  2016cites this paper
• Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

  2016cites this paper
• The Epicardium in Ventricular Septation During Evolution and Development

  2016cites this paper
• Molecular Pathways and Animal Models of Ventricular Septal Defect

  2016cites this paper
• Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles in Cardiac Progenitor Cells

  2016cites this paper
• Title Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

  2016cites this paper
• Congenital Heart Diseases: The Broken Heart

  2016cites this paper
• The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model

  2015cites this paper
• Role of Embryonic and Differentiated Cells in Cardiac Development

  2015cites this paper
• Formation and Malformation of Cardiac Trabeculae: Biological Basis, Clinical Significance, and Special Yield of Magnetic Resonance Imaging in Assessment.

  2015cites this paper