A BMP-Shh negative-feedback loop restricts Shh expression during limb development
A BMP-Shh negative-feedback loop restricts Shh expression during limb development
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DOI：
10.1242/dev.036418
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发表时间：
2009-11-15
期刊：
影响因子：
4.6
通讯作者：
Ros, Maria A.
中科院分区：
文献类型：
--
作者：
Bastida, Ma Felix;Sheth, Rushikesh;Ros, Maria A.
组织和器官的正常模式需要将信号分子严格限制在明确定义的组织中心。在肢芽中，主要的信号中心之一是极化活动区（ZPA），它通过产生音刺猬（SHH）来控制生长和模式。Shh在时间和空间上的适当表达对于正常的肢芽形成是至关重要的，因为即使是细微的修饰，也会产生重要的表型后果。然而，尽管有很多关于激活和维持Shh表达的因素的信息，但关于将其表达限制在ZPA的机制知之甚少。在这项研究中，我们发现，BMP活性负调控Shh转录和BMP-Shh负反馈回路用于限制Shh表达。通过干扰维持Shh表达的FGF和Wnt信号传导活性来实现Shh的BMP依赖性下调。我们还表明，FGF诱导的Shh需要蛋白质合成，并介导的ERK 1/2 MAPK转导途径。BMP基因在后肢芽中胚层的表达受FGF信号的正调控，并受一个自动调节环的精细调控。我们的研究强调了后肢芽中主要信号通路之间串扰的复杂性。
Normal patterning of tissues and organs requires the tight restriction of signaling molecules to well-defined organizing centers. In the limb bud, one of the main signaling centers is the zone of polarizing activity (ZPA) that controls growth and patterning through the production of sonic hedgehog (SHH). The appropriate temporal and spatial expression of Shh is crucial for normal limb bud patterning, because modifications, even if subtle, have important phenotypic consequences. However, although there is a lot of information about the factors that activate and maintain Shh expression, much less is known about the mechanisms that restrict its expression to the ZPA. In this study, we show that BMP activity negatively regulates Shh transcription and that a BMP-Shh negative-feedback loop serves to confine Shh expression. BMP-dependent downregulation of Shh is achieved by interfering with the FGF and Wnt signaling activities that maintain Shh expression. We also show that FGF induction of Shh requires protein synthesis and is mediated by the ERK1/2 MAPK transduction pathway. BMP gene expression in the posterior limb bud mesoderm is positively regulated by FGF signaling and finely regulated by an auto-regulatory loop. Our study emphasizes the intricacy of the crosstalk between the major signaling pathways in the posterior limb bud.