Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation

Abstract

Vitamin A signals play critical roles during embryonic development. In particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor ␣ (RXR␣), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXR␣ signaling in this process are unclear, because a myocardium-restricted RXR␣ mutation does not perturb heart morphogenesis. Here, we analyze a series of tissuerestricted mutations of the RXR␣ gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXR␣ signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXR␣ deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation.coronary vessels ͉ epicardium ͉ retinoids ͉ wnt ͉ FGF

PDGF‐A as an epicardial mitogen during heart development

“…Furthermore, the total level of mitogenic activity in rCM (measured by thymidine incorporation in NIH3T3 cells) was also not altered by these treatments. It is possible that our earlier results with EMC cells were in error, although we note that our general conclusions regarding the role of RA in the embryonic epicardium have been corroborated in several independent ways by other labs (Stuckmann et al, 2003;Lavine et al, 2005;Merki et al, 2005). As a possible explanation, we suspect that the phenotype of the EMC cell line may have shifted since our original investigations such that mitogen expression or secretion has become RAindependent.…”

“…RA is made by embryonic epicardium and by EMC cells, and we have proposed that RA signaling in vivo is required for the production of epicardial mitogens. Thus, mouse embryos lacking the RA receptor RXR␣ show a profoundly hypoplastic ventricular chamber wall (Sucov et al, 1994), and this phenotype is replicated (albeit to a less severe extent) in epicardium-specific RXR␣ mutants (Merki et al, 2005). With the identification of PDGF-A as a mitogen made by EMC cells, we addressed the potential role of RA in Pdgfa expression or PDGF-A secretion.…”

“…Fibroblast growth factors (FGFs) may be important, as combined mutation of the FGFR1 and FGFR2 receptor genes results in reduced regional myocardial proliferation and an underdeveloped ventricular wall (Lavine et al, 2005). Wnt9b has also been proposed as an epicardial factor (Merki et al, 2005), although its role may be more important in the formation of coronary vasculature rather than as a mitogenic signal; this may be true for FGF as well (Lavine et al, 2006). A hypoplastic ventricular chamber wall is observed in mouse knockout studies of several genes encoding regulatory or signaling components, although how these ultimately impact myocardial proliferation remains unclear.…”

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

“…Ablation of the epicardium or loss of the epicardially expressed genes, RXR␣ and BAF180, results in defects in cardiomyoblast proliferation and coronary development (Wang et al, 2004;Merki et al, 2005). Based on these data, we and others have proposed that the epicardium secretes factors that govern both of these processes Lavine et al, 2005).…”

The epicardium as modulator of the cardiac autonomic response during early development

“…Disturbing RA signaling in the epicardium by epicardial deletion of the retinoid X receptor-α (RXRα), results in defective epithelial-to-mesenchymal transition (EMT), thinning of the myocardium, disturbed coronary arteriogenesis and ventricular pre-excitation [34,35]. This phenotype is also seen after disturbance of epicardial outgrowth in avian embryos [36] and in Wt1-null mice [27,37].…”