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Published on: March 12, 2016
hoxa1a-Null Zebrafish as a Model for Studying HOXA1-Associated Heart Malformation in Bosley-Salih-Alorainy Syndrome
Hongjie Wang1,2, Jingwei He1,2, Xuemei Han1,2
1International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
Insights
HOXA1 gene mutations cause heart defects. Zebrafish lacking the homologous hoxa1a gene developed similar cardiac malformations and posterior body abnormalities, providing a model for human HOXA1-related diseases.
Area of Science:
- Developmental Biology
- Genetics
- Cardiovascular Research
Background:
- Mutations in the human HOXA1 gene are linked to Bosley-Salih-Alorainy syndrome, characterized by severe cardiovascular malformations.
- The precise role of HOXA1 in cardiac development and morphogenesis is not fully understood.
Purpose of the Study:
- To investigate the function of HOXA1 in cardiac development using zebrafish as a model organism.
- To establish a zebrafish model for studying HOXA1-associated heart malformations.
Main Methods:
- CRISPR-Cas9 gene editing was employed to create hoxa1a-null zebrafish.
- Morphological analysis, in situ hybridization, electrocardiography, and high-speed videography were used to assess cardiac and posterior body development.
- Expression patterns of hox paralogues were analyzed.
Main Results:
- Hoxa1a-null zebrafish exhibited significant heart malformations, including ventricular enlargement, myocardial thickening, increased trabeculation, outflow tract defects, and inadequate heart looping.
- Reduced cardiac output and posterior body abnormalities affecting movement were observed in the mutants.
- Compensatory upregulation of other hox paralogues was noted in hoxa1a-null fish.
Conclusions:
- The hoxa1a-null zebrafish model accurately recapitulates cardiac disease patterns seen in human HOXA1-associated malformations.
- This study enhances the understanding of hox gene function in cardiac morphogenesis and related human diseases.
Abstract:
Mutations in HOXA1 can lead to diseases such as Bosley-Salih-Alorainy syndrome, involving severe cardiovascular malformations. However, the role of HOXA1 in cardiac morphogenesis remains unclear. hoxa1a is a homologous gene to human HOXA1 in zebrafish. We used CRISPR to make hoxa1a-null zebrafish that exhibited multiple heart malformations. In situ hybridization and sections revealed the morphological changes in mutants: enlarged ventricle with thickened myocardium and increased trabeculae, intensified OFT and inadequate heart looping, with electrocardiography supporting these pathological changes. High-speed photography captured cardiac pumping and revealed a significant decrease in cardiac output. Furthermore, lacking hoxa1a led to posterior body abnormality that affected movement ability, corresponding with the motor development delay in patients. Upregulation of hox paralogues in hoxa1a-null fish implied a compensatory mechanism between hox genes. Accordingly, we successfully constructed a hoxa1a-null model with a cardiac disease pattern which occurred in human HOXA1-associated heart malformation. The study of hoxa1a in zebrafish can further promote the understanding of hox genes and related diseases.
