Abstract
Organ laterality refers to the left-right asymmetry in disposition and conformation of internal organs and is established during embryogenesis. The heart is the first organ to display visible left-right asymmetries through its left-sided positioning and rightward looping. Here, we present a new zebrafish loss-of-function allele for tbx5a, which displays defective rightward cardiac looping morphogenesis. By mapping individual cardiomyocyte behavior during cardiac looping, we establish that ventricular and atrial cardiomyocytes rearrange in distinct directions. As a consequence, the cardiac chambers twist around the atrioventricular canal resulting in torsion of the heart tube, which is compromised in tbx5a mutants. Pharmacological treatment and ex vivo culture establishes that the cardiac twisting depends on intrinsic mechanisms and is independent from cardiac growth. Furthermore, genetic experiments indicate that looping requires proper tissue patterning. We conclude that cardiac looping involves twisting of the chambers around the atrioventricular canal, which requires correct tissue patterning by Tbx5a.
Highlights
Bilateral animals such as vertebrates, while being symmetric on the outside when divided through the sagittal plane, have left-right (LR) asymmetrically arranged internal organs
Embryos were screened around 28 hpf for correct formation and asymmetry of the cardiac tube, and at 50 hpf to assess cardiac looping
To confirm that oug affects the tbx5a locus (NM_130915), we carried out a complementation test with a previously identified tbx5a mutant allele, heartstrings which was reported to display cardiac looping and fin bud formation defects (Garrity et al, 2002)
Summary
Bilateral animals such as vertebrates, while being symmetric on the outside when divided through the sagittal plane, have left-right (LR) asymmetrically arranged internal organs. The embryonic heart is the first organ to visibly break LR symmetry of the vertebrate embryo (Desgrange et al, 2018 and references therein). The heart starts out as a linear tube positioned at the midline, which subsequently bends toward the right, initiating an ensemble of developmentally regulated complex processes referred to as cardiac looping (Patten, 1922). The looped heart tube is either a flat S-shape in fish or a helix in amniotes (chick and mouse) (Desgrange et al, 2018). Correct looping is closely intertwined to proper patterning and alignment of the inflow and outflow tracts, cardiac chambers and atrioventricular canal, which are crucial to establish and maintain heart function. Cardiac looping defects in humans can result in severe congenital heart defects such as transposition of the great arteries (TGA), double outlet right ventricle (DORV), and Tetralogy of Fallot (TOF) (Lin et al, 2014)
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