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Reptilian heart development and the molecular basis of cardiac chamber evolution

Nature volume 461, pages 95–98 (2009)Cite this article

A Corrigendum to this article was published on 24 September 2009

Abstract

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 endothermy1,2,3. 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 ventricles4,5,6,7? 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 precursors8,9. 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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Figure 1: Reptilian heart development.
Figure 2: Gene expression in amniote embryos.
Figure 3: Ventricle-restricted deletion of mouse Tbx5.
Figure 4: Misexpression of Tbx5 results in loss of IVS patterning.

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Acknowledgements

We thank J. N. Wylie and L. Davidson for technical assistance, M. Harris and J. Fallon for alligator embryos, T. Sanger and J. Gibson-Brown for unpublished data on Anolis staging, T. Ogura for chick Tbx5 and Tbx20 probes, and G. Howard and S. Ordway for editorial assistance. This work was funded in part by the March of Dimes Birth Defects Foundation (B.G.B.), the J. David Gladstone Institutes (B.G.B.), William H. Younger Jr (B.G.B.); a National Institutes of Health program project grant (P01HL089707 to B.G.B., B.L.B.); scholarships from the Natural Sciences and Engineering Research Council of Canada, the Heart and Stroke Richard Lewar Centre for Excellence, University of Toronto, and Ontario Graduate Scholarship (A.D.M.); the Fumi Yamamura Memorial Foundation for Female Natural Scientists and Grants-in-Aid for Scientific Research (C) (K.K.-T.), MEXT’s program for young independent researchers (K.K.-T., J.K.T.), Sumitomo Foundation and Nakajima Foundation (J.K.T.), a Canada Research Chair in Imaging (R.M.H.), the Heart and Stroke foundation of Canada and the Canadian Institutes for Health Research (M.N.), and grants from the National Science Foundation (RUI-0748508 to S.F.G., J.C.-T. and IOS-0742833 to J.W.). Funding for the J. David Gladstone Institutes from a National Institutes of Health/ National Center for Research Resources grant (C06 RR018928) is also acknowledged.

Author Contributions K.K.-T. performed reptile histology and gene expression studies; A.D.M., B.L.K., T.S. and B.G.B. performed mouse experiments; J.C.-T. and S.F.G. obtained turtle specimens and isolated T. scripta Tbx5 complementary DNA (cDNA); S.L. and L.B. isolated Anolis specimens under direction of J.W.; B.L.K. acquired and reconstructed OPT images; R.O.G. performed Tbx5 immunohistochemistry under direction of M.N.; R.M.H. directed initial mouse embryo OPT; J.K.T. obtained chick and mouse specimens; R.O.G., M.N., B.L.B. and E.N.O. provided genetically modified mice before publication; B.G.B. conceived and directed the project, and wrote the paper. All authors contributed to the written manuscript.

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Author notes

  1. Kazuko Koshiba-Takeuchi, Alessandro D. Mori and Bogac L. Kaynak: These authors contributed equally to this work.

Authors and Affiliations

  1. Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA,

    Kazuko Koshiba-Takeuchi, Alessandro D. Mori, Bogac L. Kaynak, Tatyana Sukonnik & Benoit G. Bruneau

  2. Department of Pediatrics,,

    Kazuko Koshiba-Takeuchi, Alessandro D. Mori, Bogac L. Kaynak, Tatyana Sukonnik & Benoit G. Bruneau

  3. Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA,

    Kazuko Koshiba-Takeuchi, Alessandro D. Mori, Bogac L. Kaynak, Tatyana Sukonnik, Brian L. Black & Benoit G. Bruneau

  4. Division of Cardiovascular Research, Global-Edge Institute, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan,

    Kazuko Koshiba-Takeuchi & Jun K. Takeuchi

  5. Program in Stem Cell and Developmental Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

    Alessandro D. Mori & Benoit G. Bruneau

  6. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    Alessandro D. Mori & Benoit G. Bruneau

  7. Biology Department, Millersville University, Millersville, Pennsylvania 17551, USA,

    Judith Cebra-Thomas

  8. Institut de Recherches Cliniques de Montréal, Programme de Biologie Moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada,

    Romain O. Georges & Mona Nemer

  9. Department of Psychology and Program in Neuroscience, Michigan State University, East Lansing, Michigan 48824, USA,

    Stephany Latham, Laural Beck & Juli Wade

  10. The Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

    R. Mark Henkelman

  11. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    R. Mark Henkelman

  12. Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA,

    Brian L. Black

  13. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA,

    Eric N. Olson

  14. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5 Canada,

    Mona Nemer

  15. Department of Biology, Swarthmore College, Swarthmore, Pennsylvania 19081, USA,

    Scott F. Gilbert

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Corresponding author

Correspondence to Benoit G. Bruneau.

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Koshiba-Takeuchi, K., Mori, A., Kaynak, B. et al. Reptilian heart development and the molecular basis of cardiac chamber evolution. Nature 461, 95–98 (2009). https://doi.org/10.1038/nature08324

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