A freely diffusible form of Sonic hedgehog mediates long-range signalling
A freely diffusible form of Sonic hedgehog mediates long-range signalling
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DOI：
10.1038/35079648
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发表时间：
2001-06-01
期刊：
影响因子：
64.8
通讯作者：
Robbins, DJ
中科院分区：
文献类型：
--
作者：
Zeng, X;Goetz, JA;Robbins, DJ
分泌蛋白Sonic hedgehog(Shh)通过短程和长程信号的组合发挥其许多模式效应(1-3)。已经提出了三种不同的机制来解释Shh的长期效应，这些机制不一定是相互排斥的：Shh的简单扩散，其中Shh激活二次信号的传递机制，以及通过细胞质延伸直接传递Shh，称为细胞素。虽然有很多数据(使用可溶性重组Shh(ShhN))支持远程Shh信号(1，2)的简单扩散模型，但迄今为止几乎没有证据表明Shh的天然形式是自由扩散的，并且不与膜相关。在这里，我们提供了一种可自由扩散的Shh(S-ShhNp)形式的证据，它是胆固醇修饰的、多聚体和生物有效的。我们进一步证明，S-ShhNp的可用性受到Shh途径的两个功能拮抗剂Patted(Ptc)和Hedgehog-Interaction Protein(HIP)(4-6)的调节。最后，我们显示了S-ShhNp在雏鸡肢体前后轴上的梯度，证明了S-ShhNp的生理相关性。
The secreted protein Sonic hedgehog (Shh) exerts many of its patterning effects through a combination of short- and long-range signalling(1-3). Three distinct mechanisms, which are not necessarily mutually exclusive, have been proposed to account for the long-range effects of Shh: simple diffusion of Shh, a relay mechanism in which Shh activates secondary signals, and direct delivery of Shh through cytoplasmic extensions, termed cytonemes. Although there is much data (using soluble recombinant Shh (ShhN)) to support the simple diffusion model of long-range Shh signalling(1,2), there has been little evidence to date for a native form of Shh that is freely diffusible and not membrane-associated. Here we provide evidence for a freely diffusible form of Shh (s-ShhNp) that is cholesterol modified, multimeric and biologically potent. We further demonstrate that the availability of s-ShhNp is regulated by two functional antagonists of the Shh pathway, Patched (Ptc) and Hedgehog-interacting protein (Hip)(4-6). Finally, we show a gradient of s-ShhNp across the anterior-posterior axis of the chick limb, demonstrating the physiological relevance of s-ShhNp.