Retinoic acid signaling is essential for formation of the heart tube in Xenopus

Abstract

Retinoic acid is clearly important for the development of the heart. In this paper, we provide evidence that retinoic acid is essential for multiple aspects of cardiogenesis in Xenopus by examining embryos that have been exposed to retinoic acid receptor antagonists. Early in cardiogenesis, retinoic acid alters the expression of key genes in the lateral plate mesoderm including Nkx2.5 and HAND1, indicating that early patterning of the lateral plate mesoderm is, in part, controlled by retinoic acid. We found that, in Xenopus, the transition of the heart from a sheet of cells to a tube required retinoic acid signaling. The requirement for retinoic acid signaling was determined to take place during a narrow window of time between embryonic stages 14 and 18, well before heart tube closure. At the highest doses used, the lateral fields of myocardium fail to fuse, intermediate doses lead to a fusion of the two sides but failure to form a tube, and embryos exposed to lower concentrations of antagonist form a heart tube that failed to complete all the landmark changes that characterize looping. The myocardial phenotypes observed when exposed to the retinoic acid antagonist resemble the myocardium from earlier stages of cardiogenesis, although precocious expression of cardiac differentiation markers was not seen. The morphology of individual cells within the myocardium appeared immature, closely resembling the shape and size of cells at earlier stages of development. However, the failures in morphogenesis are not merely a slowing of development because, even when allowed to develop through stage 40, the heart tubes did not close when embryos were exposed to high levels of antagonist. Indeed, some aspects of left-right asymmetry also remained even in hearts that never formed a tube. These results demonstrate that components of the retinoic acid signaling pathway are necessary for the progression of cardiac morphogenesis in Xenopus.

Cardiopoietic Factors

“…284,285 RA is essential for heart tube formation in Xenopus. 286 Blocking RA signals during gastrulation causes an increase in cardiac progenitors. However, with continuous treatment, this increase in the cardiac pool is not sustained and a net decrease in heart size was observed at the time of cardiac differentiation.…”

Building the vertebrate heart - an evolutionary approach to cardiac development

“…The precardiac mesoderm is often described as a cardiac crescent (horseshoeshaped area) located cranially to the prechordal plate that extends from the right to the left side crossing the midline from very early on (Rosenquist, 1970). This is still accepted to be the case of the mammalian HFs, but recent studies suggest that avian and amphibian embryos have two HFs (left and right) that remain separated for a significant period of time (Colas et al, 2000;Collop et al, 2006). Some authors decided to consider the left and right HF populations as two independent fields (Kirby, 2002) but for the sake of simplicity we will consider them as only one.…”

Id genes are essential for early heart formation

“…Intense research over the past two decades has led to the identification of extracellular signals that initiate cardiogenesis (Schultheiss et al 1997;Marvin et al 2001;Schneider and Mercola 2001;Pandur et al 2002;Collop et al 2006;Kattman et al 2006;Foley et al 2007;Laflamme et al 2007;Yang et al 2008;Lian et al 2013). In contrast, current knowledge of the intracellular mediators controlling this process is very fragmentary.…”