The function of retinoic acid (RA) during limb development is still debated, as loss and gain of function studies led to opposite conclusions. With regard to limb initiation, genetic studies demonstrated that activation of FGF10 signaling is required for the emergence of limb buds from the trunk, with Tbx5 and RA signaling acting upstream in the forelimb field, whereas Tbx4 and Pitx1 act upstream in the hindlimb field. Early studies in chick embryos suggested that RA as well as Meis1 and Meis2 (Meis1/2) are required for subsequent proximodistal patterning of both forelimbs and hindlimbs, with RA diffusing from the trunk, functioning to activate Meis1/2 specifically in the proximal limb bud mesoderm. However, genetic loss of RA signaling does not result in loss of limb Meis1/2 expression and limb patterning is normal, although Meis1/2 expression is reduced in trunk somitic mesoderm. More recent studies demonstrated that global genetic loss of Meis1/2 results in a somite defect and failure of limb bud initiation. Other new studies reported that conditional genetic loss of Meis1/2 in the limb results in proximodistal patterning defects, and distal FGF8 signaling represses Meis1/2 to constrain its expression to the proximal limb. In this review, we hypothesize that RA and Meis1/2 both function in the trunk to initiate forelimb bud initiation, but that limb Meis1/2 expression is activated proximally by a factor other than RA and repressed distally by FGF8 to generate proximodistal patterning.

中文翻译：

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维甲酸信号，FGF信号和Meis基因在肢体发育控制中的作用

维甲酸（RA）在肢体发育过程中的功能仍存在争议，因为功能研究的丧失和获得导致相反的结论。关于肢体启动，遗传研究表明，从树干出现肢芽需要FGF10信号的激活，而Tbx5和RA信号在前肢场中上游起作用，而Tbx4和Pitx1在后肢场中上游起作用。早期对雏鸡胚胎的研究表明，RA和Meis1和Meis2（Meis1 / 2）对于随后的前肢和后肢近端眼部图案形成均是必需的，RA从躯干扩散，从而激活Meis1 / 2特别是在近肢芽中皮。然而，尽管躯干体中胚层的Meis1 / 2表达降低，但RA信号的遗传丧失不会导致肢体Meis1 / 2表达丧失，并且肢体模式正常。最近的研究表明，Meis1 / 2的全球遗传损失会导致躯体缺陷和肢芽萌发失败。其他新研究报告说，肢体中Meis1 / 2的有条件遗传损失会导致近现代性模式缺陷，而远端FGF8信号传导会抑制Meis1 / 2，以限制其在近端肢体中的表达。在这篇评论中，我们假设RA和Meis1 / 2两者都在躯干中启动前肢芽的启动，但肢体Meis1 / 2表达被RA以外的其他因子激活，并被FGF8远端抑制以产生近现代模式。