Netrin-1 attracts axons through FAK-dependent mechanotransduction.
Netrin-1 attracts axons through FAK-dependent mechanotransduction.
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DOI：
10.1523/jneurosci.0999-12.2012
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发表时间：
2012-08-22
期刊：
影响因子：
--
通讯作者：
Sheetz MP
中科院分区：
文献类型：
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作者：
Moore SW;Zhang X;Lynch CD;Sheetz MP
细胞外信号影响引导轴突的细胞内生化级联的机制很重要，但知之甚少。由于轴突延伸的力学性质，我们探索了生长锥体与其引导线索的物理相互作用是否可能涉及其中。在小鼠脊髓连合神经元对netrin-1的轴突吸引的背景下，我们发现netrin-1与底物的机械连接是轴突生长、生长锥扩张、轴突吸引以及粘着斑激酶(FAK)和Crk相关底物(CAS)磷酸化所必需的。肌球蛋白II的活性对于网织蛋白-1上的牵引力>；30PN是必需的。有趣的是，虽然这些肌球蛋白II依赖于Netrin-1底物或微球的作用力是增加FAK的激酶活性和磷酸化所必需的，但它们并不是Netrin-1增加CAS磷酸化所必需的。当FAK激酶活性被抑制时，生长锥招募额外的粘连和在netrin-1上产生力量>；60pN的能力被破坏。综上所述，这些发现证明了机械转导在化学吸引Netrin-1过程中的重要作用，并且FAK的机械激活加强了与Netrin-1的相互作用，从而施加了更大的力。
The mechanism by which extracellular cues influence intracellular biochemical cascades that guide axons is important, yet poorly understood. Because of the mechanical nature of axon extension, we explored whether the physical interactions of growth cones with their guidance cues might be involved. In the context of mouse spinal commissural neuron axon attraction to netrin-1, we found that mechanical attachment of netrin-1 to the substrate was required for axon outgrowth, growth cone expansion, axon attraction and phosphorylation of focal adhesion kinase (FAK) and Crk-associated substrate (CAS). Myosin II activity was necessary for traction forces >30 pN on netrin-1. Interestingly, while these myosin II-dependent forces on netrin-1 substrates or beads were needed to increase the kinase activity and phosphorylation of FAK, they were not necessary for netrin-1 to increase CAS phosphorylation. When FAK kinase activity was inhibited, the growth cone’s ability to recruit additional adhesions and to generate forces >60 pN on netrin-1 was disrupted. Together, these findings demonstrate an important role for mechanotransduction during chemoattraction to netrin-1 and that mechanical activation of FAK reinforces interactions with netrin-1 allowing greater forces to be exerted.