Retinoic acid deficiency alters second heart field formation

Abstract

Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2 ؊/؊ knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2 ؊/؊ embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2 ؊/؊ embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2 ؊/؊ mutant heart, in a gene dosage-dependent manner.retinoids ͉ retinaldehyde dehydrogenase 2 ͉ heart development ͉ Nkx2.5 ͉ FGF8

Fate of retinoic acid–activated embryonic cell lineages

“…4A). This pattern is virtually identical to that reported for the RARE-hsp68-lacZ transgene at these stages (Moss et al, 1998;Ryckebusch et al, 2008). During further branchial arch development (E8.5-E9.5), streams of labeled cells were observed along the third, fourth, and sixth arches (Fig.…”

“…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.…”

“…This would provide important information with respect to various developing systems, including the brain (Dupe et al, 1999;Smith et al, 2001;Sirbu et al, 2005;Ribes et al, 2006;Molotkova et al, 2007), sensory organs Matt et al, 2005;Molotkov et al, 2006;Romand et al, 2006), cranial neural crest cells and branchial arch derivatives (Wendling et al, 2000;Niederreither et al, 2003;Mark et al, 2004), and heart (Merki et al, 2005;Ryckebusch et al, 2008;Sirbu et al, 2008). Retinoids are also potent teratogenic compounds in human (Lammer et al, 1985;Hanson and Leachman, 2001;Charakida et al, 2004, and references therein), and excess RA administration affects many morphogenetic processes in mice (e.g., Kessel and Gruss, 1991;Marshall et al, 1992;Shum et al, 1999;Matt et al, 2003).…”

BMP and RA signaling cooperate to regulate Apolipoprotein C1 expression during embryonic development

“…The crosstalk between RA and BMP pathways varies depending on the context of different systems (Means and Gudas, 1995). For example, during the neural development in chicken, RA signaling inhibits BMP-regulated proliferation and differentiation of neural progenitor cells through suppressing BMP signaling (Sheng et al, 2010); during second heart field formation in mouse, RA up-regulated cardiac Bmp expression at the looping stage (Ryckebusch et al, 2008); RA and BMP signaling exhibited both antagonistic and synergistic effects on the osteogenesis of bone marrow stromal cells (Bi et al, 2013). In our case, apoc1 expression is cooperated by BMP and RA signaling pathways during zebrafish development.…”

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

“…During early cardiogenesis, RALDH2 is expressed in relation to the sinoatrial precursors expression, indicating that RA may be synthesis along the anteriorposterior axis of the heart tube [278,279]. Inhibition of the RALDH2 in mouse embryos showed abnormally distribution of second heart field genes (such as Isl1, Tbx1, Fgf10, and Fgf8) in a posterior direction [280,281]. In avian cardiac morphogenesis, the expression of RALDH2 in the posterior region is coinciding to the activation of atrial specific myosin heavy chain 1 (AMHC1) gene, a marker of atrial phenotype [282].…”