Sonic Hedgehog Guides Axons through a Noncanonical, Src-Family-Kinase-Dependent Signaling Pathway
Sonic Hedgehog Guides Axons through a Noncanonical, Src-Family-Kinase-Dependent Signaling Pathway
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DOI：
10.1016/j.neuron.2009.03.022
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发表时间：
2009-05-14
期刊：
影响因子：
16.2
通讯作者：
Charron, Frederic
中科院分区：
文献类型：
--
作者：
Yam, Patricia T.;Langlois, Sebastien D.;Charron, Frederic
声波刺猬 (Shh) 在细胞命运规范和轴突引导等发育事件中发挥着重要作用。 Shh 通过转录介导的经典 Shh 信号传导诱导细胞命运规范。然而，Shh 引导轴突的机制尚不清楚。为了研究这一点，我们开发了一种用于轴突引导的体外测定，其中可以在对化学线索的定义梯度做出反应的同时对神经元进行成像。置于Shh梯度中的分离连合神经元的轴突迅速转向增加Shh浓度。与这种快速反应一致，我们发现“嘘”的吸引不需要转录。相反，Shh 以 Smoothened 依赖性方式刺激 Src 家族激酶 (SFK) 成员的活性。此外，SFK 活性是 Shh 介导的连合轴突引导所必需的，但不是诱导 Gli 转录报告活性所必需的。总之，这些结果表明 Shh 通过快速作用的非规范信号通路来引导轴突。
Sonic hedgehog (Shh) plays essential roles in developmental events such as cell fate specification and axon guidance. Shh induces cell fate specification through canonical Shh signaling, mediated by transcription. However, the mechanism by which Shh guides axons is unknown. To study this, we developed an in vitro assay for axon guidance, in which neurons can be imaged while responding to a defined gradient of a chemical cue. Axons of dissociated commissural neurons placed in a Shh gradient turned rapidly toward increasing concentrations of Shh. Consistent with this rapid response, we showed that attraction by Shh does not require transcription. Instead, Shh stimulates the activity of Src family kinase (SFK) members in a Smoothened-dependent manner. Moreover, SFK activity is required for Shh-mediated guidance of commissural axons, but not for induction of Gli transcriptional reporter activity. Together, these results indicate that Shh acts via a rapidly acting, noncanonical signaling pathway to guide axons.