Moss J B, Xavier-Neto J, Shapiro M D, Nayeem S M, McCaffery P, Dräger U C, Rosenthal N
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown 02129, USA.
Dev Biol. 1998 Jul 1;199(1):55-71. doi: 10.1006/dbio.1998.8911.
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.
视黄酸（RA）因其对心脏的致畸作用而与心脏形态发生有关，尽管其在正常心脏发生中的作用尚不清楚。为了确定RA在心脏形态发生中的作用参数，我们分析了发育中的小鼠心脏中配体合成、反应和失活的模式。将由RA反应元件（RARE）控制的lacZ转基因的激活与视黄醛氧化脱氢酶RALDH2（小鼠胚胎中最早的RA合成酶）的定位以及编码RA降解酶（P450RA）的基因的表达进行了比较。我们观察到，在心脏发育过程中，RALDH2的定位和RA反应几乎是重叠的。最初，RALDH2和RARE-LacZ活性都局限于未环化心脏的静脉窦，但在背侧心内膜中较高，而P450RA的表达局限于心内膜。后期的特征是RALDH2积累和RA反应从静脉窦到心房、背内侧圆锥动脉干、主动脉弓和心外膜的连续、不连续进展。RA反应的这种动态模式是局部RALDH2的直接结果，因为培养胚胎的心脏对外源性RA刺激具有一致的反应能力。这些观察结果支持了一个模型，即内源性RA对心脏发育的影响取决于配体的局部呈现，其合成来源的扩散有限。
