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.
Highlights
Nodal signaling in the left lateral plate mesoderm (LPM) upregulates the expression of the homeobox gene Pitx2 [50], which is expressed in the developing organs, including the heart, and has been proposed to transduce the “left” molecular information into asymmetric cardiac morphogenesis, as we will discuss in the following paragraphs
More recent data highlight the complexity of this process since differential cell migration is regulated by integrated, but different, actions of Nodal signaling in the left myocardial region and of BMP signaling in the right endocardial region, via a common target, the transcription factor FoxH1 [56]
It is recognized that three concatenated steps lead to cardiac laterality
Summary
Nodal signaling in the left LPM upregulates the expression of the homeobox gene Pitx2 [50], which is expressed in the developing organs, including the heart, and has been proposed to transduce the “left” molecular information into asymmetric cardiac morphogenesis, as we will discuss in the following paragraphs. The expression of this set of genes defines the so called “Nodal signaling cascade”, which is a conserved feature of distinct species, from fish to mice [51], with the noticeable exception of chickens, where Lefty expression is missing [44]
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