Current Perspectives in Cardiac Laterality

Abstract

The heart is the first organ to break symmetry in the developing embryo and onset of dextral looping is the first indication of this event. Looping is a complex process that progresses concomitantly to cardiac chamber differentiation and ultimately leads to the alignment of the cardiac regions in their final topology. Generation of cardiac asymmetry is crucial to ensuring proper form and consequent functionality of the heart, and therefore it is a highly regulated process. It has long been known that molecular left/right signals originate far before morphological asymmetry and therefore can direct it. The use of several animal models has led to the characterization of a complex regulatory network, which invariably converges on the Tgf-β signaling molecule Nodal and its downstream target, the homeobox transcription factor Pitx2. Here, we review current data on the cellular and molecular bases of cardiac looping and laterality, and discuss the contribution of Nodal and Pitx2 to these processes. A special emphasis will be given to the morphogenetic role of Pitx2 and to its modulation of transcriptional and functional properties, which have also linked laterality to atrial fibrillation.

Keywords: Pitx2; atrial identity; heart laterality; heart looping; left/right asymmetry; nodal.

Figure 1

Comparison of Pitx2 mRNA expression in mouse (a–c), chicken (d–f) and zebrafish embryos (g,g’). Mice and chicken, single in situ hybridization (ISH); zebrafish, double ISH: Pitx2, dark blue, and mlc2v, magenta. Note that in chickens and mice, Pitx2 delineates the left heart primordium and its remodeling. In developing zebrafish hearts, Pitx2 expression delineates the common atrium and is regionalized in the ventricles. vv: vitelline veins. Panels a–f are reproduced with permission from [85].

Figure 2

The recognized role of Pitx2 and Nodal in modulation of the two components of cardiac laterality. Top boxes: looping and asymmetric remodeling; the illustrations show the developmental repositioning of the left/right portions of the linear heart (blue/yellow color) with looping progression and, aside, the underlying driving processes. They are initially driven by Nodal in early cardiomyocytes, then reinforced by Pitx2 during development. Bottom box: left–right (L/R) atrial identity; the underlying characteristics, which are under the control of Pitx2, are indicated aside. CM: cardiomyocyte; ECM: extracellular matrix.