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Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

Author

Listed:
  • Mengmeng Huang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Alexander A. Akerberg

    (Boston Children’s Hospital
    Harvard Medical School)

  • Xiaoran Zhang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Haejin Yoon

    (Blavatnik Institute, Harvard Medical School
    Ulsan National Institute of Science and Technology)

  • Shakchhi Joshi

    (Blavatnik Institute, Harvard Medical School)

  • Celia Hallinan

    (Boston Children’s Hospital)

  • Christopher Nguyen

    (Harvard Medical School
    Massachusetts General Hospital
    Athinoula A Martinos Center for Biomedical Imaging
    Heart Vascular & Thoracic Institute, Cleveland Clinic)

  • William T. Pu

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Marcia C. Haigis

    (Blavatnik Institute, Harvard Medical School)

  • C. Geoffrey Burns

    (Boston Children’s Hospital
    Harvard Medical School)

  • Caroline E. Burns

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

Abstract

Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. Prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. In contrast to current models, we demonstrate that these structural deficits arise secondary to impaired pump function as these phenotypes are rescued when Rbfox is specifically expressed in the myocardium. Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores cardiovascular development in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects.

Suggested Citation

  • Mengmeng Huang & Alexander A. Akerberg & Xiaoran Zhang & Haejin Yoon & Shakchhi Joshi & Celia Hallinan & Christopher Nguyen & William T. Pu & Marcia C. Haigis & C. Geoffrey Burns & Caroline E. Burns, 2022. "Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32982-x
    DOI: 10.1038/s41467-022-32982-x
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    References listed on IDEAS

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    1. Samir Zaidi & Murim Choi & Hiroko Wakimoto & Lijiang Ma & Jianming Jiang & John D. Overton & Angela Romano-Adesman & Robert D. Bjornson & Roger E. Breitbart & Kerry K. Brown & Nicholas J. Carriero & Y, 2013. "De novo mutations in histone-modifying genes in congenital heart disease," Nature, Nature, vol. 498(7453), pages 220-223, June.
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