Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.
Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.
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DOI：
10.1371/journal.pgen.1003689
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Waxman JS
中科院分区：
文献类型：
--
作者：
D'Aniello E;Rydeen AB;Anderson JL;Mandal A;Waxman JS
正常的胚胎发育和组织稳态需要精确水平的视黄酸（RA）信号。尽管适当的胚胎RA信号水平的重要性，潜在的先天性缺陷，由于RA信号的扰动的机制还没有完全理解。在这里，我们报告了缺乏RA受体αb1（RARαb1）（一种保守的RAR剪接变体）的斑马鱼胚胎具有增大的心脏和增加的心肌细胞（CM）特化，这是令人惊讶的RA信号增加的结果。重要的是，RARαb2的消耗或RARαb1和RARαb2的同时消耗也导致RA信号传导增加，表明这种效应是RAR消耗的更广泛后果。RARαb1和Cyp26a1（一种促进RA降解的酶）的同时耗竭以及新型转基因RA传感器系的使用支持了以下假设：RAR缺陷胚胎中RA信号的增加是胚胎RA增加与补偿性RAR表达偶联的结果。我们的研究结果支持了一个有趣的新机制，通过该机制，RARs的缺失会导致一个以前未被认识到的正反馈回路，该回路可导致胚胎RA致畸性增加导致发育缺陷。视黄酸（RA）是维生素A最活跃的代谢产物。在所有脊椎动物中，适当水平的RA对于适当的胚胎发育和组织维持是必需的。人类胚胎中不适当的RA水平会导致影响许多器官的先天性缺陷，包括心脏和四肢，并导致多种类型的癌症。因此，了解动物如何保持适当的RA水平和不适当的RA信号传导的后果将提供对人类先天性缺陷和疾病的深入了解。RA信号传导由RA受体（RAR）介导，RA受体是在结合RA时被激活的转录因子。我们发现，斑马鱼中RAR的缺失会导致缺陷，令人惊讶的是，这些缺陷是由于胚胎RA的增加而不是RA信号传导的缺陷。我们的研究结果是第一个证明RAR耗竭elevants的正反馈机制，促进RA信号通过补充增加胚胎RA和RAR的表达。因此，我们的分析为维持适当的RA信号传导所需的分子机制提供了新的见解，并将积极影响我们对先天性缺陷机制的理解。
Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA. Retinoic acid (RA) is the most active metabolic product of Vitamin A. Appropriate levels of RA are required for proper embryonic development and tissue maintenance in all vertebrates. Inappropriate levels of RA in human embryos can cause congenital defects that affect many organs, including the heart and limbs, and lead to numerous types of cancers. Understanding how animals maintain appropriate RA levels and the consequences of inappropriate RA signaling will therefore provide insight into human congenital defects and diseases. RA signaling is mediated by RA receptors (RARs), which are transcription factors that are activated when binding RA. We have found that depletion of RARs in zebrafish results in defects that are surprisingly due to increases in embryonic RA and not a deficiency of RA signaling. Our results are the first to demonstrate that RAR depletion elicits a positive feedback mechanism that promotes RA signaling through complementary increases in both embryonic RA and RAR expression. Therefore, our analysis provides novel insight into the molecular mechanisms that are required to maintain appropriate RA signaling and will positively impact our understanding of the mechanisms underlying congenital defects.
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影响因子：
2.7
作者：
He X;Yan YL;Eberhart JK;Herpin A;Wagner TU;Schartl M;Postlethwait JH
通讯作者：
Postlethwait JH
影响因子：
4.6
作者：
Cai, Anna Q.;Radtke, Kelly;Schilling, Thomas F.
通讯作者：
Schilling, Thomas F.
影响因子：
2.7
作者：
Davison, Jon M.;Akitake, Courtney M.;Parsons, Michael J.
通讯作者：
Parsons, Michael J.
DOI：
10.1073/pnas.88.22.10138
发表时间：
1991-11-01
影响因子：
11.1
作者：
LEROY, P;NAKSHATRI, H;CHAMBON, P
通讯作者：
CHAMBON, P
影响因子：
9.2
作者：
Mably, JD;Mohideen, MAPK;Fishman, MC
通讯作者：
Fishman, MC