Retinoic Acid Promotes Limb Induction through Effects on Body Axis Extension but Is Unnecessary for Limb Patterning
Retinoic Acid Promotes Limb Induction through Effects on Body Axis Extension but Is Unnecessary for Limb Patterning
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DOI：
10.1016/j.cub.2009.04.059
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发表时间：
2009-06-23
期刊：
影响因子：
9.2
通讯作者：
Duester, Gregg
中科院分区：
文献类型：
--
作者：
Zhao, Xianling;Sirbu, Ioan Ovidiu;Duester, Gregg
视黄酸（RA）被认为是参与肢芽模式沿着近远轴或前后轴的关键信号分子，分别通过诱导Meis 2和Shh发挥作用[1]。在这里，我们利用缺乏RA合成的Raldh 2（-/-）和Raldh 3（-/-）小鼠胚胎[2]来证明RA信号传导对于Shh和Meis 2的肢体表达不是必需的。我们表明，RA的行动是必需的肢体领域以外的身体轴在前肢诱导，但RA是不必要的，在后期阶段，当后肢萌芽和图案发生。我们提供了躯干中胚层RA作用模型的证据，其中前肢诱导需要RA抑制发育中躯干中的Fgf 8，类似于RA控制体节发生[3，4]和心脏发育[5]。我们证明，胸鳍发育RA缺陷的斑马鱼胚胎可以获救的FGF受体拮抗剂SU 5402。此外，胚胎ChIP测定证明RA受体在体内结合Fgf 8启动子。我们的研究结果表明，RA信号是不需要的肢体proximodistal或前后图案，但RA抑制FGF 8信号在体轴延伸的早期阶段提供了一个环境允许诱导前肢芽。
Retinoic acid (RA) is thought to be a key signaling molecule involved in limb bud patterning along the proximodistal or anteroposterior axes functioning through induction of Meis2 and Shh, respectively [1]. Here, we utilize Raldh2(-/-) and Raldh(3-/-) mouse embryos lacking RA synthesis [2] to demonstrate that RA signaling is not required for limb expression of Shh and Meis2. We demonstrate that RA action is required outside of the limb field in the body axis during forelimb induction but that RA is unnecessary at later stages when hindlimb budding and patterning occur. We provide evidence for a model of trunk mesodermal RA action in which forelimb induction requires RA repression of Fgf8 in the developing trunk similar to how RA controls somitogenesis [3, 4] and heart development [5]. We demonstrate that pectoral fin development in RA-deficient zebrafish embryos can be rescued by an FGF receptor antagonist SU5402. In addition, embryo ChIP assays demonstrate that RA receptors bind the Fgf8 promoter in vivo. Our findings suggest that RA signaling is not required for limb proximodistal or anteroposterior patterning but that RA inhibition of FGF8 signaling during the early stages of body axis extension provides an environment permissive for induction of forelimb buds.