PUBLICATION
Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
- Authors
- Huang, M., Akerberg, A.A., Zhang, X., Yoon, H., Joshi, S., Hallinan, C., Nguyen, C., Pu, W.T., Haigis, M.C., Burns, C.G., Burns, C.E.
- ID
- ZDB-PUB-221007-1
- Date
- 2022
- Source
- Nature communications 13: 5877 (Journal)
- Registered Authors
- Burns (Erter), Caroline
- Keywords
- none
- Datasets
- GEO:GSE189934
- MeSH Terms
-
- Animals
- Humans
- Hypoplastic Left Heart Syndrome*/genetics
- Hypoplastic Left Heart Syndrome*/pathology
- Myocardium/metabolism
- RNA Splicing Factors/genetics
- RNA Splicing Factors/metabolism
- RNA, Messenger/metabolism
- RNA-Binding Proteins/metabolism
- Repressor Proteins/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 36198703 Full text @ Nat. Commun.
Citation
Huang, M., Akerberg, A.A., Zhang, X., Yoon, H., Joshi, S., Hallinan, C., Nguyen, C., Pu, W.T., Haigis, M.C., Burns, C.G., Burns, C.E. (2022) Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome. Nature communications. 13:5877.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping