Yam Patricia T, Langlois Sébastien D, Morin Steves, Charron Frédéric
Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada.
Neuron. 2009 May 14;62(3):349-62. doi: 10.1016/j.neuron.2009.03.022.
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.
音猬因子（Shh）在诸如细胞命运决定和轴突导向等发育事件中发挥着重要作用。Shh通过由转录介导的经典Shh信号传导诱导细胞命运决定。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导向的体外测定法，在该测定法中，神经元在对化学信号的特定梯度做出反应时可以进行成像。置于Shh梯度中的解离连合神经元的轴突迅速转向Shh浓度增加的方向。与这种快速反应一致，我们表明Shh的吸引不需要转录。相反，Shh以一种依赖于Smoothened的方式刺激Src家族激酶（SFK）成员的活性。此外，SFK活性是Shh介导的连合轴突导向所必需的，但不是Gli转录报告基因活性诱导所必需的。总之，这些结果表明Shh通过一条快速作用的非经典信号通路来引导轴突。
