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

Mengmeng Huang, Alexander A. Akerberg, Xiaoran Zhang, Haejin Yoon, Shakchhi Joshi, Celia Hallinan, Christopher Nguyen, William T. Pu, Marcia C. Haigis, C. Geoffrey Burns () and Caroline E. Burns ()
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Mengmeng Huang: Boston Children’s Hospital
Alexander A. Akerberg: Boston Children’s Hospital
Xiaoran Zhang: Boston Children’s Hospital
Haejin Yoon: Blavatnik Institute, Harvard Medical School
Shakchhi Joshi: Blavatnik Institute, Harvard Medical School
Celia Hallinan: Boston Children’s Hospital
Christopher Nguyen: Harvard Medical School
William T. Pu: Boston Children’s Hospital
Marcia C. Haigis: Blavatnik Institute, Harvard Medical School
C. Geoffrey Burns: Boston Children’s Hospital
Caroline E. Burns: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32982-x

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