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Updated: Aug 26, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
Mengmeng Huang1,2, Alexander A Akerberg1,2, Xiaoran Zhang1,2
1Division of Basic and Translational Cardiovascular Research, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
Insights
Hypoplastic left heart syndrome (HLHS) is linked to RNA binding protein RBFOX2. Zebrafish lacking RBFOX2 show HLHS-like defects, revealing intrinsic myocardial dysfunction as a key cause.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect.
- Current understanding suggests HLHS results from multiple genes and phenotypes.
Purpose of the Study:
- To investigate the role of RNA binding protein RBFOX2 in HLHS pathogenesis.
- To explore the underlying mechanisms of cardiovascular defects in HLHS.
Main Methods:
- Utilized zebrafish models lacking RBFOX2 orthologs to study cardiovascular development.
- Assessed the impact of Rbfox expression in the myocardium on structural deficits.
- Analyzed gene expression and alternative splicing of sarcomere and mitochondrial components.
- Tested the rescue efficacy of human RBFOX2 mRNA and HLHS-linked variants.
Main Results:
- Zebrafish lacking RBFOX2 orthologs exhibited HLHS-overlapping cardiovascular defects.
- Structural deficits were secondary to impaired myocardial pump function, rescued by Rbfox myocardial expression.
- Diminished expression and alternative splicing of sarcomere and mitochondrial genes were observed.
- Human RBFOX2 mRNA rescued defects, while HLHS-linked variants did not.
Conclusions:
- RBFOX2 plays a critical role in myocardial development and function.
- Intrinsic myocardial defects, rather than solely multigenic factors, are central to HLHS pathogenesis.
- This study supports a new paradigm for HLHS involving RBFOX2 and myocardial dysfunction.
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.
