Axon guidance is a critical process in forming the connections between a neuron and its target. The growth cone steers the growing axon toward the appropriate direction by integrating extracellular guidance cues and initiating intracellular signal transduction pathways downstream of these cues. The growth cone generates these responses by remodeling its cytoskeletal components. Regulation of microtubule dynamics within the growth cone is important for making guidance decisions. TACC3, as a microtubule plus‐end binding (EB) protein, modulates microtubule dynamics during axon outgrowth and guidance. We have previously shown that Xenopus laevis embryos depleted of TACC3 displayed spinal cord axon guidance defects, while TACC3‐overexpressing spinal neurons showed increased resistance to Slit2‐induced growth cone collapse. Tyrosine kinases play an important role in relaying guidance signals to downstream targets during pathfinding events via inducing tyrosine phosphorylation. Here, in order to investigate the mechanism behind TACC3‐mediated axon guidance, we examined whether tyrosine residues that are present in TACC3 have any role in regulating TACC3's interaction with microtubules or during axon outgrowth and guidance behaviors. We find that the phosphorylatable tyrosines within the TACC domain are important for the microtubule plus‐end tracking behavior of TACC3. Moreover, TACC domain phosphorylation impacts axon outgrowth dynamics such as growth length and growth persistency. Together, our results suggest that tyrosine phosphorylation of TACC3 affects TACC3's microtubule plus‐end tracking behavior as well as its ability to mediate axon growth dynamics in cultured embryonic neural tube explants.

中文翻译：

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调查轴突生长和指导过程中，TACC3的TACC域内酪氨酸残基的磷酸化状态对微管行为的影响。

轴突引导是形成神经元与其靶标之间联系的关键过程。生长锥通过整合细胞外引导线索并在这些线索的下游启动细胞内信号转导途径，将生长中的轴突导向适当的方向。生长锥通过重塑其细胞骨架成分来产生这些反应。生长锥内微管动力学的调节对于制定指导决策很重要。TACC3作为微管末端结合（EB）蛋白，可在轴突生长和引导过程中调节微管动力学。我们之前已经证明非洲爪蟾耗尽TACC3的胚胎显示脊髓轴突引导缺陷，而过表达TACC3的脊髓神经元显示出对Slit2诱导的生长锥塌陷的抵抗力增强。酪氨酸激酶在寻路事件期间通过诱导酪氨酸磷酸化将指导信号传递至下游靶标中发挥重要作用。在这里，为了研究TACC3介导的轴突引导的机制，我们检查了TACC3中存在的酪氨酸残基是否在调节TACC3与微管的相互作用或在轴突生长和引导行为中发挥任何作用。我们发现，TACC域内的可磷酸化酪氨酸对于TACC3的微管正负追踪行为很重要。此外，TACC域磷酸化影响轴突生长动力学，例如生长长度和生长持久性。