Transient Nodal Signaling in Left Precursors Coordinates Opposed Asymmetries Shaping the Heart Loop

Heart Development and Congenital Structural Heart Defects

“…Thus, Nodal is necessary not only to control the direction of the heart loop (normally rightward) but also to shape the loop. In keeping with this finding, mice and patients with Nodal pathogenic variants do not display situs inversus; instead, they exhibit complex CHDs, including transposition of the great arteries (TGA), DORV, and atrioventricular septal defects (AVSDs) (96,32). In the absence of Nodal in the mouse, four categories of embryonic heart loop shapes are produced, with the right ventricle cranial to the left, and in all possible lateral configurations (right/left ventricle positioned on the right/right, left/left, left/right, or right/left sides, respectively) (Figure 5).…”

“…Another patterning important for heart morphogenesis is left/right, initiated in the left/right organizer and mediated mainly by the secreted factor Nodal (105). Precisely timed gene expression analyses and drug treatments have shown that Nodal is required at E8.5c-d (i.e., before the formation of the heart tube) to specify a left identity in myocardial precursor cells (32). DiI labeling (34), clonal analyses (71,72), and genetic tracing of Nodal (32) enable the contributions of the left/right second heart field to be traced: At E9.5, left precursors contribute to the left sinus venosus, the dorsal left atrium, the superior atrioventricular canal, and the left outflow tract, and at E14.5, they contribute to the left superior caval vein, the pulmonary vein, the left atrium, and the pulmonary trunk.…”

“…Signaling by the left determinant Nodal does not interfere with the buckling mechanism; rather, it is essential for the amplification and coordination of left/right asymmetries at the heart tube poles (32). Thus, Nodal is necessary not only to control the direction of the heart loop (normally rightward) but also to shape the loop.…”

“…The left origin of this primary atrial septum is shown by a transgenic marker that reports signaling by the left determinant Nodal (39). In Nodal mouse mutants, atrial septation is consistently absent, in association with right atrial isomerism (32). At the leading edge of the muscular primary atrial septum, an endocardial thickening, referred to as the mesenchymal cap (8), progresses until fusion with the atrioventricular cushions.…”

“…In the case of the heterotaxy syndrome, which has been clearly associated with anomalies in the formation and function of the left/right organizer (44,114,128), the origin of the phenotypic variability of associated CHDs remains poorly understood. In the mouse, a single-gene inactivation is associated with a spectrum of defects, some of which have partial penetrance (32,33). This points to the need to uncover the mechanisms of asymmetric organogenesis beyond the left/right bias provided by the left/right organizer.…”