Abstract
For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’. ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.
Highlights
An understanding of heart development is important for the treatment of both congenital and acquired heart disease
We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function
Generation of the list of zebrafish heart jogging genes A list of 30 zebrafish genes that affect heart jogging was compiled using a variety of approaches.Twelve zebrafish proteins were identified as they were already annotated to the ‘heart jogging’ Gene Ontology (GO) terms, the remaining 18 proteins were identified using the ZFIN Site Search, with the search phrase ‘heart jogging’, and filtering using the ‘Expression/Phenotypes’ category
Summary
An understanding of heart development is important for the treatment of both congenital and acquired heart disease. The majority of heart development studies use model organisms for ethical and practical reasons. Transparent fish embryos, as well chick embryos, enable the developing heart to be studied in real time[1], and the mouse continues to be a key model organism used to investigate mammalian heart development[2]. For the majority of developing vertebrate embryos left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish[4,5]. Laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, and the direction of heart jogging and heart looping. Cilia within the Kuppfer’s vesicle are known to be instrumental in establishing left-right asymmetry and play a significant role in determining the direction of heart jogging[7] and heart looping[8]. Several of the genes involved in zebrafish heart jogging have been identified from mutation, morpholino and functional complementation studies[6,10,13,14,15,16,17,18,19,20,21,22,23,24,25,26]
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