expression of genes associated with atrial left-right morphogenesis in mouse embryos treated with retinoic acid

视黄酸（RA）处理妊娠小鼠胚胎日（ED） 6.5诱导约30%的胚胎右同分异构体、异常环和房室垫发育不良，其中常伴有单侧心室发育不全。在这类胚胎中，由于室间隔和房室垫之间的不对齐，通向发育不全脑室的房室孔通常狭窄。典型的AV垫有三个裂片，而不是正常的两个大裂片和两个小裂片。在本研究中，我们通过体内观察和心室面积测量以及形态学检查来评估ra处理胚胎的心室运动。活体胚胎心脏运动的体内观察使我们能够准确地评估心室容积，而不像标准形态学检查那样受固定状态的影响，并将其与心室动力学相关联。单侧心室发育不全的进展与特征性流入道异常和流入障碍有关。此外，A类病例中，1例仅出现单侧流入延迟，另外5例同时出现单侧脑室发育不全和流入延迟，提示流入障碍可能先于脑室发育不全的进展。因此，左心室发育不全合并脾功能不全综合征可能是由左心室流入受限引起的，并伴有房室缓冲层发育不良。接下来，我们检测了在视黄酸处理的坝体胚胎中nodal和left的表达。这两种基因都在左侧和/或右侧以斑点和马赛克模式表达，而正常胚胎则在左侧以连续模式表达基因。表达的周期是改变的和可变的。综上所述，维甲酸诱导的心脏异常是由基因表达改变和心内血流动力学引起的。

Retinoic acid (RA) treatment of pregnant mouse at embryonic day (ED) 6.5 induces right isomerism, anomalous looping and AV cushion dysplasia in about 30% of the embryos, in which unilateral ventricular hypoplasia was often associated. In such embryos, AV orifice to the hypoplastic ventricle was usually stenotic because of malalignment between the interventriclar septum and AV cushion. AV cushion has three lobes in the typical cases, instead of two major and two minor lobes in the normal ones. In the present study, we evaluated the ventricular motion in the RA-treated embryos by in-vivo observation and ventricular area measurement followed by morphological examination. In-vivo observation of the cardiac motion of live embryos enabled us to accurately evaluate the ventricular volume, not influenced by fixation state as in the standard morphological examination, and to correlate it with the ventricular dynamics. The progress of unilateral ventricular hypoplasia was associated with characteristic inflow tract anomaly and inflow disturbance. Furthermore, among cases of category A, one case had only unilateral inflow delay and the other 5 cases had both unilateral ventriclar hypoplasia and inflow delay, suggesting that inflow disturbance is likely to precede the progress of ventriclar hypoplasia. Thus, left ventricular hypoplasia with asplenia syndrome might be caused by inflow restriction to the left venrticle associated with AV cushion dysplasia. Next, we examined the expression of nodal and lefty in the somite stage embryos from dams treated with retinoic acid. Both genes were expressed on left and/or right side and in a sptted and mosaic pattern, in contrast to normal embryos who express the genes on the left side in a continuous pattern. The period of expression was altered and variable. In summary, retinoic acid-induced cardiac anomaly was caused by altered gene expression and intracardiac hemodynamics.