The Kinesin-2 Family Member KIF3C Regulates Microtubule Dynamics and Is Required for Axon Growth and Regeneration
The Kinesin-2 Family Member KIF3C Regulates Microtubule Dynamics and Is Required for Axon Growth and Regeneration
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DOI：
10.1523/jneurosci.5221-12.2013
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发表时间：
2013-07-10
影响因子：
5.3
通讯作者：
Fawcett, James W.
中科院分区：
文献类型：
--
作者：
Gumy, Laura F.;Chew, Daniel J.;Fawcett, James W.
损伤后轴突再生需要生长锥中微管细胞骨架的广泛重建、重组和稳定。在这里，我们确定KIF3C作为轴突生长和再生的关键调节因子，通过控制生长锥中的微管动力学和组织。KIF3C是发育调节的。大鼠胚胎的感觉轴突和生长锥中含有检测不到的KIF3C蛋白，该蛋白在损伤后立即局部翻译。在成年神经元中，KIF3C从细胞体轴突运输，并在生长锥富集，在那里它优先结合酪氨酸化微管。在功能上，KIF3C与EB3的相互作用对于其在生长锥中的微管加端的定位是必要的。在成年神经元中KIF3C的耗尽导致稳定的、过度生长的和环状的微管增加，因为微管灾难频率的强烈降低，这表明KIF3C作为微管不稳定因子起作用。通过RNA干扰或KIF3C基因敲除，缺乏KIF3C的成年轴突在体外显示受损的轴突生长，并且在体外和体内损伤后延迟再生。敲除KIF3C的小鼠胚胎轴突正常生长，但在损伤后不能再生，因为它们不能局部翻译KIF3C。这些数据表明，KIF3C是一种损伤特异性驱动蛋白，通过调节和组织生长锥中的微管细胞骨架来促进轴突生长和再生。
Axon regeneration after injury requires the extensive reconstruction, reorganization, and stabilization of the microtubule cytoskeleton in the growth cones. Here, we identify KIF3C as a key regulator of axonal growth and regeneration by controlling microtubule dynamics and organization in the growth cone. KIF3C is developmentally regulated. Rat embryonic sensory axons and growth cones contain undetectable levels of KIF3C protein that is locally translated immediately after injury. In adult neurons, KIF3C is axonally transported from the cell body and is enriched at the growth cone where it preferentially binds to tyrosinated microtubules. Functionally, the interaction of KIF3C with EB3 is necessary for its localization at the microtubule plus-ends in the growth cone. Depletion of KIF3C in adult neurons leads to an increase in stable, overgrown and looped microtubules because of a strong decrease in the microtubule frequency of catastrophes, suggesting that KIF3C functions as a microtubule-destabilizing factor. Adult axons lacking KIF3C, by RNA interference or KIF3C gene knock-out, display an impaired axonal outgrowth in vitro and a delayed regeneration after injury both in vitro and in vivo. Murine KIF3C knock-out embryonic axons grow normally but do not regenerate after injury because they are unable to locally translate KIF3C. These data show that KIF3C is an injury-specific kinesin that contributes to axon growth and regeneration by regulating and organizing the microtubule cytoskeleton in the growth cone.