A molecular basis for retinoic acid-induced axial truncation
A molecular basis for retinoic acid-induced axial truncation
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DOI：
10.1006/dbio.1998.9110
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发表时间：
1999-01-01
影响因子：
2.7
通讯作者：
Lohnes, D
中科院分区：
文献类型：
--
作者：
Iulianella, A;Beckett, B;Lohnes, D
饮食剥夺和基因破坏研究清楚地表明，具有生物活性的类维生素A，例如视黄酸（RA），对于许多发育计划至关重要。类似的个体发育过程也受到视黄酸过量的影响，这表明类视黄醇给药的影响反映了正常的视黄酸依赖性事件。在小鼠中，根据治疗的发育阶段，外源性视黄酸可诱发前部（无脑畸形、外脑畸形）和后部（脊柱裂）神经管缺陷。视黄酸受体γ（RARγ）在交配后8.5天介导对尾神经管的这些影响，因为RARγ（-/-）小鼠在此阶段对视黄酸诱导的脊柱裂完全具有抵抗力。因此，我们使用这种无效小鼠作为模型，通过使用一组信息标记并比较视黄酸处理的野生型和 RAR gamma(-/-) 胚胎之间的表达来检查视黄醇诱导的尾部神经管缺陷的分子性质。我们的研究结果表明，野生型胚胎的处理导致所有检查的中胚层标记（例如brachyury、wnt-3a、cdx-4）的尾部表达快速显着降低，而体节、神经上皮、脊索、底板和后肠标记不受影响。 RAR gamma(-/-) 突变体对所有检查的标记物均表现出正常的表达模式，这与中胚层缺陷是视黄醇诱导的脊柱裂病因学基础的观点一致。我们还发现，后闪族胚胎组织中含有可检测到的生物活性视黄醇，但尾侧前成体胚胎组织中没有，这一观察结果与尾侧外植体快速清除外源性 RA 的能力相关。有趣的是，编码mP450RAI（一种细胞色素P450，其产物被认为分解代谢视黄酸的产物）的转录本在尾部胚胎的类视黄酸缺乏区域中丰富，mP450RAI在体内被视黄酸处理迅速诱导，这与之前的研究一致，表明它在类视黄酸信号传导中发挥着关键作用。这些数据表明新生中胚层对视黄酸高度敏感，并且 mP450RAI 可以严格调节尾部胚胎中的类视黄醇水平。这些发现还提出了一种可能性，即 RA 可能部分通过影响 brachyury 表达而在后中胚层衍生物的生成中发挥作用。 (C) 1999 年学术出版社。
Dietary deprivation and gene disruption studies clearly demonstrate that biologically active retinoids, such as retinoic acid (RA), are essential for numerous developmental programs. Similar ontogenic processes are also affected by retinoic acid excess, suggesting that the effects of retinoid administration reflect normal retinoid-dependent events. In the mouse, exogenous retinoic acid can induce both anterior (anencephaly, exencephaly) and posterior (spina bifida) neural tube defects depending on the developmental stage of treatment. Retinoic acid receptor gamma (RAR gamma) mediates these effects on the caudal neural tube at 8.5 days postcoitum, as RAR gamma(-/-) mice are completely resistant to spina bifida induced by retinoic acid at this stage. We therefore used this null mouse as a model to examine the molecular nature of retinoid-induced caudal neural tube defects by using a panel of informative markers and comparing their expression between retinoic acid-treated wild-type and RAR gamma(-/-) embryos. Our findings indicate that treatment of wild-type embryos led to a rapid and significant decrease in the caudal expression of all mesodermal markers examined (e.g., brachyury, wnt-3a, cdx-4), whereas somite, neuroepithelial, notochord, floorplate, and hindgut markers were unaffected. RAR gamma(-/-) mutants exhibited normal expression patterns for all markers examined, consistent with the notion that mesodermal defects underlie the etiology of retinoid-induced spina bifida. We also found that posterior semitic, but not caudal presomitic, embryonic tissues contained detectable bioactive retinoids, an observation which correlated with the ability of caudal explants to rapidly clear exogenous RA. Interestingly, transcripts encoding mP450RAI, a cytochrome P450, the product of which is believed to catabolize retinoic acid, were abundant in the retinoid-poor region of the caudal embryo, mP450RAI was rapidly induced by retinoic acid treatment in vivo, consistent with previous studies suggesting that it plays a critical role in retinoid signaling. These data suggest that nascent mesoderm is highly sensitive to retinoic acid and that mP450RAI serves to tightly regulate retinoid levels in the caudal embryo. These findings also raise the possibility that RA may play a role in the generation of posterior mesoderm derivatives in part by affecting brachyury expression. (C) 1999 Academic Press.