Src Family Kinases Are Required for Limb Trajectory Selection by Spinal Motor Axons
Src Family Kinases Are Required for Limb Trajectory Selection by Spinal Motor Axons
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DOI：
10.1523/jneurosci.0265-09.2009
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发表时间：
2009-04-29
影响因子：
5.3
通讯作者：
Kania, Artur
中科院分区：
文献类型：
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作者：
Kao, Tzu-Jen;Palmesino, Elena;Kania, Artur
轴突生长锥体上引导受体的信号传递是组装功能神经系统必不可少的过程。我们研究了在脊髓外侧运动柱(LMC)运动轴突向腹侧或背侧肢体间充质投射的背景下，作为生长锥引导信号中间体的Src家族激酶(SFK)的体内功能。通过原位mRNA检测，我们发现在肢体运动轨迹选择时，鸡和小鼠胚胎的LMC运动神经元表达了Src和Fyn。在鸡LMC轴突中过表达的CSK抑制SFK活性，导致LMC轴突在肢体间充质内选择了不适当的背腹轨迹，内侧LMC轴突投射到肢体背侧和腹侧神经，具有明显的随机性。我们还在Src突变小鼠中检测到LMC轴突轨迹选择错误，证明了Src在运动轴突引导中的非冗余作用，这与鸡LMC神经元中导致LMC轴突重定向的Src功能的获得和丧失是一致的。最后，CSK介导的SFK抑制减弱了EphA或EphB过表达引起的LMC轴突的重定向，暗示SFK参与了Eph介导的LMC运动轴突导引。综上所述，我们的研究结果表明，SFK对于运动轴突导引是必不可少的，并表明它们在传递EPhin信号方面发挥着重要作用，Eph信号介导了肢体运动轴突轨迹的选择。
Signal relay by guidance receptors at the axonal growth cone is a process essential for the assembly of a functional nervous system. We investigated the in vivo function of Src family kinases (SFKs) as growth cone guidance signaling intermediates in the context of spinal lateral motor column (LMC) motor axon projection toward the ventral or dorsal limb mesenchyme. Using in situ mRNA detection we determined that Src and Fyn are expressed in LMC motor neurons of chick and mouse embryos at the time of limb trajectory selection. Inhibition of SFK activity by C-terminal Src kinase (Csk) overexpression in chick LMC axons using in ovo electroporation resulted in LMC axons selecting the inappropriate dorsoventral trajectory within the limb mesenchyme, with medial LMC axon projecting into the dorsal and ventral limb nerve with apparently random incidence. We also detected LMC axon trajectory choice errors in Src mutant mice demonstrating a nonredundant role for Src in motor axon guidance in agreement with gain and loss of Src function in chick LMC neurons which led to the redirection of LMC axons. Finally, Csk-mediated SFK inhibition attenuated the retargeting of LMC axons caused by EphA or EphB over-expression, implying the participation of SFKs in Eph-mediated LMC motor axon guidance. In summary, our findings demonstrate that SFKs are essential for motor axon guidance and suggest that they play an important role in relaying ephrin: Eph signals that mediate the selection of motor axon trajectory in the limb.