DYNAMIC PATTERNS OF RETINOIC ACID SYNTHESIS AND RESPONSE IN THE DEVELOPING MAMMALIAN HEART

Retinoic acid (RA) has been implicated in cardiac morphogenesis by its teratogenic effects on the heart, although its role in normal cardiog enesis remains unknown. To define the parameters of RA action in cardi ac morphogenesis, we analyzed the patterns of ligand synthesis, respon se, and inactivation in the developing mouse heart. Activation of a la cZ transgene controlled by an RA response element (RARE) was compared to the localization of the retinaldehydeoxidizing dehydrogenase RALDH2 , the earliest RA synthetic enzyme in the mouse embryo, and to the exp ression of a gene encoding an RA-degrading enzyme (P450RA). We observe d that RALDH2 localization and RA response were virtually superimposab le throughout heart development. Initially, both RALDH2 and RARE-LacZ activity were restricted to the sinus venosa in unlooped hearts, but w ere high in the dorsal mesocardium, while P450RA expression was restri cted to the endocardium. Later stages were characterized by a sequenti al, noncontiguous progression of RALDH2 accumulation and RA response, from the sinus venosa to atria, dorsal-medial conotruncus, aortic arch es, and the epicardium. This dynamic pattern of RA response was a dire ct result of localized RALDH2 since hearts of cultured embryos were un iformly competent to respond to an exogenous RA challenge. These obser vations support a model in which the influence of endogenous RA on hea rt development depends upon localized presentation of the ligand, with only limited diffusion from the source of its synthesis. (C) 1998 Aca demic Press.