ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons
ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons
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DOI：
10.1523/jneurosci.1409-12.2012
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发表时间：
2012-07-25
影响因子：
5.3
通讯作者：
Fawcett, James W.
中科院分区：
文献类型：
--
作者：
Eva, Richard;Crisp, Sarah;Fawcett, James W.
整合素参与轴突生长和再生。整合素的操作是促进轴突再生和理解CNS再生失败的途径。α 9整合素的表达促进轴突再生，因此我们研究了α 9 β 1在轴突和生长锥中的运输和转运。我们以前已经发现，α 9和β 1整合素交通通过Rab11阳性循环内体在外周轴突和生长锥。然而，通过Rab11的运输是缓慢的，而快速运输发生在缺乏Rab11的囊泡中。我们进一步研究了α 9和β 1整合素的运输和交通在成年大鼠背根神经节轴突和PC12细胞。整合素在快速轴突运输和生长锥运输期间存在于ARF6囊泡中。我们报告说，这些整合素的快速轴突运输和它们在细胞表面的贩运是由ARF6调节。通过表达ACAP1导致的ARF6失活导致β 1整合素向神经元表面的再循环增加，并导致顺行轴突运输增加。通过表达神经元鸟嘌呤核苷酸交换因子ARNO或EFA 6激活ARF6，增加轴突中的逆行整合素转运并增加整合素内化。ARF 6的失活增加了整合素介导的生长，而激活则减少了它。ARF 6的激活或失活引起的整合素转运和再循环的协调变化是这种轴突生长调节背后的可能机制。我们的数据表明，在外周轴突的整合素交通和运输的一种新的机制，调节的激活状态的ARF6，并建议ARF6可能是有针对性的，以增强损伤后的整合素依赖性轴突再生。
Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of alpha 9 integrin promotes axon regeneration, so we have investigated alpha 9 beta 1 trafficking and transport in axons and at the growth cone. We have previously found that alpha 9 and beta 1 integrins traffic via Rab11-positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied alpha 9 and beta 1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of beta 1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury.