A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

“…Treatment with retinoic acid causes an anterior expansion of the inflow and a commensurate decrease in the outflow that is similar, but substantially more severe, to that caused by deleting mef2c (Xavier-Neto et al, 1999;Davis et al, 2001;Hochgreb et al, 2003). In addition to the morphological similarities, shared changes in gene expression are the reduced domain of the ventriclespecific mlc2v gene and the anterior expansion of the sinoatrial-enriched tbx5 gene (Xavier-Neto et al, 1999;Liberatore et al, 2000).…”

“…These studies imply that RA treatment or deletion of mef2c alters the fate of cardiomyocytes from the outflow to the inflow. A generally accepted interpretation of the RA studies is that outflow cardiomyocytes are the default pathway of cardiomyocyte differentiation and that RA actively directs differentiation into the inflow lineage (Hochgreb et al, 2003). By analogy, this suggests a model for MEF2C function in segment specification in which it actively promotes outflow-specific differentiation and directs cells to be non-responsive to the inflow-specifying actions of RA.…”

“…These two segments will be further subdivided as development progresses with the inflow segment being subdivided into the sinus venosus and atria, and the outflow into the OFT, ventricles, and AVC. The precise mechanism directing this specification is not known in any detail, but considerable evidence supports a model in which the default pathway for cardiomyocyte differentiation is to the outflow segment, with retinoic acid (RA) directing immature cardiomyocytes to the inflow (Yutzey et al, 1994;Niederreither et al, 2001;Hochgreb et al, 2003;Simoes-Costa et al, 2005). The downstream molecules regulating differentiation of both segments are unknown, yet it is likely that transcription factors play a prominent role.…”

Fate of retinoic acid–activated embryonic cell lineages

“…These include (i) the ''first heart field'' or cardiac crescent formed from mesoderm emerging from the primitive streak (Garcia-Martinez and Schoenwolf, 1993;Tam et al, 1997); (ii) the ''second heart field'' originating from pharyngeal mesoderm (Buckingham et al, 2005); (iii) the (pro)epicardium, a population originating and giving rise to coronary vasculature, myocardial fibroblasts and to a distinct cardiomyocytic lineage (Cai et al, 2008;Zhou et al, 2008), and (iv) the ''cardiac'' neural crest, a subset of post-otic neural crest cells migrating through the third to sixth branchial arches and participating to the development of the aortic arches and aorticopulmonary septum (reviewed by Rochais et al, 2009). All these lineages have been reported to be influenced by embryonic RA (Hochgreb et al, 2003;Ryckebusch et al, 2008;Sirbu et al, 2008;Dupe and Pellerin, 2009), although recent studies implicate the second heart field (Ryckebusch et al, 2008;Sirbu et al, 2008) and the epicardium (Merki et al, 2005;Lin et al, 2010) as the main sites of RA signaling.…”

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

“…RA treatment of HH stage 4 cardiogenic tissue activates the expression of the atrium-specific gene AMHC1 in anterior progenitors fated to develop into out-flow track tissues [20]. Furthermore, in both mouse and chicken embryos, inhibition of RA signaling within critical periods produces embryos with oversized ventricles and smaller or missing atria, and the exogenous addition of RA results in reverted phenotypes [21,22]. Furthermore, studies with mouse embryonic stem cells indicate that retinoic acid promotes the expression of atrial-related genes [23].…”