Dynamic Patterns of Retinoic Acid Synthesis and Response in the Developing Mammalian Heart

Abstract

Retinoic acid (RA) has been implicated in cardiac morphogenesis by its teratogenic effects on the heart, although its role in normal cardiogenesis remains unknown. To define the parameters of RA action in cardiac morphogenesis, we analyzed the patterns of ligand synthesis, response, and inactivation in the developing mouse heart. Activation of a lacZ transgene controlled by an RA response element (RARE) was compared to the localization of the retinaldehyde-oxidizing dehydrogenase RALDH2, the earliest RA synthetic enzyme in the mouse embryo, and to the expression of a gene encoding an RA-degrading enzyme (P450RA). We observed that RALDH2 localization and RA response were virtually superimposable throughout heart development. Initially, both RALDH2 and RARE-LacZ activity were restricted to the sinus venosa in unlooped hearts, but were high in the dorsal mesocardium, while P450RA expression was restricted to the endocardium. Later stages were characterized by a sequential, noncontiguous progression of RALDH2 accumulation and RA response, from the sinus venosa to atria, dorsal-medial conotruncus, aortic arches, and the epicardium. This dynamic pattern of RA response was a direct result of localized RALDH2, since hearts of cultured embryos were uniformly competent to respond to an exogenous RA challenge. These observations support a model in which the influence of endogenous RA on heart development depends upon localized presentation of the ligand, with only limited diffusion from the source of its synthesis.

Fate of retinoic acid–activated embryonic cell lineages

“…1E-G; see below for details). Altogether, RARE-hsp68-driven Cre excision is, therefore, consistent with the known pattern of activity of the RAREhsp68-lacZ transgene in the embryonic trunk, cervical, and rostral head regions (Rossant et al, 1991;Moss et al, 1998;Mic et al, 2002Mic et al, , 2004aRibes et al, 2006).…”

“…1D; details about the distribution of labeled cells are given in the next sections). Again, this spatial distribution strikingly mimics the pattern of activity of the RAREhsp68-lacZ transgene (Rossant et al, 1991;Moss et al, 1998;Ribes et al, 2009;Uehara et al, 2009;Supp. Fig .…”

The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells

“…These first areas to become covered are the AV and conoventricular (CV) grooves resulting in the formation of a characteristic set of epicardial cuffs in these intersegmental areas. Subsequently, the epicardium spreads over the rest of the myocardial surface (Vrancken Peeters et al, 1995;Moss et al, 1998;Xavier-Neto et al, 2000).…”

“…This is important since retinoic acid is known to be essential in cardiac development (Dyson et al, 1995;Gruber et al, 1996;Kastner et al, 1997;Niederreither et al, 2000;Chen et al, 2002;Stuckmann et al, 2003). Furthermore, it has been demonstrated that retinoic acid is actively synthesized by RALDH2 in the epicardiums of both mammals and avians (Moss et al, 1998;Xavier-Neto et al, 2000;Pérez-Pomares et al, 2002b). Thus the interaction between WT1 and RALDH2 likely plays a critical role in the differentiation of the EPDC.…”

Cardiac patterning and morphogenesis in zebrafish

“…Studies in chick and mouse have implicated retinoic acid (RA) signaling as a positive influence on atrial development (Yutzey et al, 1994;Moss et al, 1998;Fig. 3.…”