Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx

Abstract

Morphogenesis of the cardiac arterial pole is dependent on addition of myocardium and smooth muscle from the secondary heart field and septation by cardiac neural crest cells. Cardiac neural crest ablation results in persistent truncus arteriosus and failure of addition of myocardium from the secondary heart field leading to malalignment of the arterial pole with the ventricles. Previously, we have shown that elevated FGF signaling after neural crest ablation causes depressed Ca2+ transients in the primary heart tube. We hypothesized that neural crest ablation results in elevated FGF8 signaling in the caudal pharynx that disrupts secondary heart field development. In this study, we show that FGF8 signaling is elevated in the caudal pharynx after cardiac neural crest ablation. In addition, treatment of cardiac neural crest-ablated embryos with FGF8b blocking antibody or an FGF receptor blocker rescues secondary heart field myocardial development in a time- and dose-dependent manner. Interestingly, reduction of FGF8 signaling in normal embryos disrupts myocardial secondary heart field development, resulting in arterial pole malalignment. These results indicate that the secondary heart field myocardium is particularly sensitive to FGF8 signaling for normal conotruncal development, and further, that cardiac neural crest cells modulate FGF8 signaling in the caudal pharynx.

Retinoic acid deficiency alters second heart field formation

“…The importance of Fgf8 in SHF signaling has been noted (19,20,22,37,38). Our study indicates that a primary mechanism by which RA regulates SHF dynamics may be by modulating FGF signaling.…”

“…Accordingly, FGFs can only elicit cardiomyogenic effects in regions where BMP signaling is also present (40). Alternately, the expanded early FGF8 signaling may hinder the capacity of the prospective myocardial SHF cells to develop and correctly function, similar to what is observed at slightly later stages when excess FGF8 resulting from cardiac neural crest ablation disrupts myocardial function (37,41). Moreover, altering RA-Fgf8 regulatory interactions may produce adverse consequences.…”

β-Catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis

“…Cardiac neural crest cells are also required for outflow tract morphogenesis and can affect proliferation of the secondary heart field (41, 42). We have not observed expression of Isl1 in Wnt1-Cre;R26R-lacZ lineage-traced cardiac neural crest cells within the outflow tract, although Isl1 is expressed within intrinsic cardiac ganglia, which derive from the cardiac neural crest (3,(39)(40)(41)43). From this observation, and a comparison of results with Wnt1-Cre and Isl1-Cre (Y.…”

“…Decreased proliferation within the secondary/anterior heart field has been demonstrated to result in outflow tract defects (39,40). Because Isl1 expression is down-regulated in ␤-catenin mutants and because Isl1 is required for proliferation within the secondary/ anterior heart field (4), it is likely that decreased Isl1 expression in the secondary/anterior heart field and its derivatives, as observed here, are contributing to observed outflow tract defects.…”

Gestational stress induces the unfolded protein response, resulting in heart defects

“…The proliferation of SHF cells is controlled by FGF and β-catenin/WNT signaling, and their subsequent differentiation is controlled by BMP and non-canonical WNT pathways. Perturbation of proliferation, or premature activation of differentiation or apoptosis, for example by conditional deletion of FGF signaling components in the SHF, results in OFT elongation, alignment and septation defects (Hutson et al, 2006;Ilagan et al, 2006;Park et al, 2006). In humans such defects include membranous ventricular septal defects (VSDs), persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), transposition of the great arteries (TGA), overriding aorta (OA) and tetralogy of Fallot (TOF), and account for as much as 30-60% of all human CHD (Thom et al, 2006;Bruneau, 2008).…”