Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses.
Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses.
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DOI：
10.1523/jneurosci.1542-09.2009
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发表时间：
2009-09-16
期刊：
影响因子：
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通讯作者：
Kuruvilla R
中科院分区：
文献类型：
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作者：
Ascaño M;Richmond A;Borden P;Kuruvilla R
轴突靶向营养受体是神经元对细胞外发育线索的反应的关键，但潜在的运输机制仍不清楚。在这里，我们报告说，Trk受体的靶源性神经营养因子通过transcytiosis在交感神经元中顺行贩运到轴突。使用区室化的文化，我们表明，神经元索马表面上的成熟受体被内吞和remobilized通过Rab11阳性回收内体进入轴突。动力蛋白依赖性内吞作用的抑制破坏了轴突中TrkA受体的顺行运输和定位。通过局部作用于远端轴突的神经生长因子（NGF）增强顺行TrkA递送和胞吐到轴突生长锥中。干扰内吞再循环减弱了神经生长因子依赖的信号和轴突生长，而增强再循环赋予神经元对神经生长因子的敏感性增加。我们的研究结果揭示了调控转胞吞作用作为一种意想不到的Trk贩运模式，用于快速动员已合成的受体到生长锥，从而提供了一种正反馈机制，通过该机制，限制靶源性神经营养因子的浓度增强神经元的敏感性。
Axonal targeting of trophic receptors is critical for neuronal responses to extracellular developmental cues, yet the underlying trafficking mechanisms remain unclear. Here, we report that Trk receptors for target-derived neurotrophins are anterogradely trafficked to axons via transcytosis in sympathetic neurons. Using compartmentalized cultures, we show that mature receptors on neuronal soma surfaces are endocytosed and remobilized via Rab11-positive recycling endosomes into axons. Inhibition of dynamin-dependent endocytosis disrupted anterograde transport and localization of TrkA receptors in axons. Anterograde TrkA delivery and exocytosis into axon growth cones is enhanced by nerve growth factor (NGF), acting locally on distal axons. Perturbing endocytic recycling attenuated NGF-dependent signaling and axon growth, while enhancing recycling conferred increased neuronal sensitivity to NGF. Our results reveal regulated transcytosis as an unexpected mode of Trk trafficking that serves to rapidly mobilize ready-synthesized receptors to growth cones, thus providing a positive feedback mechanism by which limiting concentrations of target-derived neurotrophins enhance neuronal sensitivity.