Zebrafish retinoic acid receptors function as context-dependent transcriptional activators.
Zebrafish retinoic acid receptors function as context-dependent transcriptional activators.
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DOI：
10.1016/j.ydbio.2011.01.022
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发表时间：
2011-04-01
影响因子：
2.7
通讯作者：
Yelon D
中科院分区：
文献类型：
--
作者：
Waxman JS;Yelon D
RA受体（RAR）被认为通过二元阻遏物-激活物机制起作用：在配体不存在的情况下，它们作为转录阻遏物起作用，并且在配体存在的情况下，它们作为转录激活物起作用。RAR机制的这种流行模型主要来自体外研究，尚未在发育背景下进行广泛测试。在这里，我们调查是否斑马鱼RAR的功能作为转录激活因子或抑制剂在早期胚胎前后图案。野生型斑马鱼RAR的异位表达不会破坏胚胎模式，也不会使胚胎对RA治疗敏感，这表明RAR的可用性在胚胎中不受限制。相反，过度活跃的斑马鱼RAR的异位表达诱导RA应答报告转基因的表达以及内源性RA应答靶基因的异位表达。然而，显性负性斑马鱼RAR的异位表达未能诱导与RA信号丢失一致的胚胎表型，尽管它们在异源细胞培养测定中具有作为转录阻遏物的功能。总之，我们的研究表明，斑马鱼RAR功能是上下文依赖性的，并且在早期模式化过程中，斑马鱼RAR主要作为转录激活因子发挥作用，并且可能仅具有最小的作为转录抑制因子的能力。因此，RAR功能的二元模型似乎不适用于所有体内情况。考虑到RA信号在被囊动物和四足动物的研究，我们提出了一个简约的模型，在脊索动物前后图案的RAR功能的演变。
RA receptors (RARs) have been thought to function through a binary repressor-activator mechanism: in the absence of ligand, they function as transcriptional repressors, and, in the presence of ligand, they function as transcriptional activators. This prevailing model of RAR mechanism has been derived mostly from in vitro studies and has not been widely tested in developmental contexts. Here, we investigate whether zebrafish RARs function as transcriptional activators or repressors during early embryonic anterior-posterior patterning. Ectopic expression of wild-type zebrafish RARs does not disrupt embryonic patterning and does not sensitize embryos to RA treatment, indicating that RAR availability is not limiting in the embryo. In contrast, ectopic expression of hyperactive zebrafish RARs induces expression of a RA-responsive reporter transgene as well as ectopic expression of endogenous RA-responsive target genes. However, ectopic expression of dominant negative zebrafish RARs fails to induce embryonic phenotypes that are consistent with loss of RA signaling, despite their ability to function as transcriptional repressors in heterologous cell culture assays. Together, our studies suggest that zebrafish RAR function is context-dependent and that, during early patterning, zebrafish RARs function primarily as transcriptional activators and may only have minimal ability to act as transcriptional repressors. Thus, it seems that the binary model for RAR function does not apply to all in vivo scenarios. Taking into account studies of RA signaling in tunicates and tetrapods, we propose a parsimonious model of the evolution of RAR function during chordate anterior-posterior patterning.
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影响因子：
2.7
作者：
Canestro, Cristian;Postlethwait, John H.
通讯作者：
Postlethwait, John H.
影响因子：
64.8
作者：
CHEN, JD;EVANS, RM
通讯作者：
EVANS, RM
影响因子：
1.2
作者：
Hale, LA;Tallafuss, A;Postlethwait, JH
通讯作者：
Postlethwait, JH
影响因子：
2.7
作者：
Feng, L.;Hernandez, R. E.;Waxman, J. S.;Yelon, D.;Moens, C. B.
通讯作者：
Moens, C. B.
DOI：
10.1073/pnas.90.7.2989
发表时间：
1993-04-01
影响因子：
11.1
作者：
DAMM, K;HEYMAN, RA;EVANS, RM
通讯作者：
EVANS, RM