RETINOIC ACID RECEPTOR BETA-2 MESSENGER-RNA IS ELEVATED BY RETINOIC ACID INVIVO IN SUSCEPTIBLE REGIONS OF MIDGESTATION MOUSE EMBRYOS
RETINOIC ACID RECEPTOR BETA-2 MESSENGER-RNA IS ELEVATED BY RETINOIC ACID INVIVO IN SUSCEPTIBLE REGIONS OF MIDGESTATION MOUSE EMBRYOS
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DOI：
10.1002/aja.1001940309
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发表时间：
1992-07-01
影响因子：
2.5
通讯作者：
SOPRANO, DR
中科院分区：
文献类型：
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作者：
HARNISH, DC;JIANG, H;SOPRANO, DR
视黄酸的许多生物效应是由其核受体（RAR-α、RAR-β 和 RAR-γ）介导的，这三种受体均以多种亚型存在。作为确定是否有任何受体亚型参与视黄酸 (RA) 处理后小鼠胚胎中诱导的畸形发生的第一步，我们检查了正常和 RA 处理胚胎的肢芽和其他胚胎区域中每种 RAR 的几种亚型的 mRNA 水平。妊娠第 11 天的小鼠接受 RA 治疗后 3 至 6 小时内，整个胚胎中的 RAR-β2 mRNA 水平增加了 7 倍，而 RAR-α2 和 RAR-gamma1 mRNA 水平仅升高了 2 倍。由于对第 11 天胚胎进行 RA 治疗，几乎每个胚胎都会产生肢体缺陷，因此我们接下来分别检查了各个胚胎区域。肢芽中 RAR-β2 mRNA 水平最高升高（12 倍），而头部/颅面部区域中等升高（8 倍），身体其他部位小幅升高（4 倍）。相比之下，所有这些组织中 RAR-alpha2 和 RAR-gamma1 mRNA 水平均升高至相似程度，仅增加了约 2 倍。视黄醇是胚胎中 RA 的前体，也能够提高肢芽中的 RAR-β2 mRNA 水平，但这种增加是延迟的，这显然表明视黄醇代谢转化为 RA 先于对 mRNA 水平的影响。最后，在妊娠第 14 天（胚胎对 RA 相对不敏感的时期）对母鼠进行治疗，导致 RAR-α2 mRNA 水平没有升高，但 RAR-β2 mRNA 水平的升高大大降低（所有胚胎区域为 2 至 3 倍）。因此，RAR-β2 mRNA 的升高与胚胎区域（例如肢芽）密切相关，而肢芽是 RA 诱导的畸胎发生的特定目标。这些结果与 RAR 的特定异构体（特别是 RAR-132）可能在异常发育过程中介导 RA 的影响的可能性是一致的。
Many of the biological effects of retinoic acid are mediated by its nuclear receptors (RAR-alpha, RAR-beta, and RAR-gamma), and each of these three receptors exist in multiple isoforms. As a first step to identify if any of the receptor isoforms are involved in dysmorphogenesis which is induced in mouse embryos after treatment with retinoic acid (RA), we examined the levels of mRNA of several isoforms of each RAR in the limb buds and other embryonic regions of normal and RA-treated embryos. Within 3 to 6 hr after treatment of mice on day 11 of gestation with RA, RAR-beta2 mRNA levels in the whole embryo increased 7-fold while both RAR-alpha2 and RAR-gamma1 mRNA levels were elevated only 2-fold. Since RA treatment of day 11 embryos especially produces limb defects in virtually every embryo, we next examined individual embryonic regions separately. Limb buds showed the highest elevations in RAR-beta2 mRNA levels (12-fold) compared to a moderate elevation in the head/craniofacial region (8-fold) and a small elevation in the remainder of the body (4-fold). In contrast, RAR-alpha2 and RAR-gamma1 mRNA levels were elevated in all these tissues to a similar extent, which amounted to only about a 2-fold increase. Retinol, the precursor of RA in the embryo, was also capable of elevating RAR-beta2 mRNA levels in the limb bud, but the increase was delayed, apparently indicating that metabolic conversion of retinol to RA preceded the effect on mRNA levels. Finally, treatment of dams on day 14 of gestation, a time when embryos are relatively insensitive to RA, resulted in no elevation in RAR-alpha2 mRNA levels and a greatly reduced elevation (2- to 3-fold in all embryonic regions) in RAR-beta2 mRNA levels. Therefore, the elevation in RAR-beta2 mRNA correlates well with regions of the embryo, e.g., limb buds, which are specific targets for RA-induced teratogenesis. These results are consistent with the possibility that specific isoforms of the RARs, in particular RAR-132, may mediate the effects of RA during abnormal development.