Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway
Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway
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DOI：
10.1038/nn919
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发表时间：
2002-10-01
影响因子：
25
通讯作者：
Holt, CE
中科院分区：
文献类型：
--
作者：
Shewan, D;Dwivedy, A;Holt, CE
视网膜轴突由Netrin-1引导出眼睛，Netrin-1是一种在视神经头分泌的诱人的指导信号。然而，在视路中，netrin-1在排除视网膜轴突生长的区域表达。这表明，轴突对netrin-1的反应可能会随着它们在通路中的前进而改变。事实上，在我们在非洲爪哇的全路径准备过程中，随着视网膜轴突从路径的远端逐渐出现，从吸引到排斥的逐渐变化发生了。我们还发现，在没有通路经验的培养中老化的轴突经历了类似的变化，这与环磷酸腺苷(CAMP)和Netrin-1受体表达的下降有关。环状AMP提升器和腺苷A2B受体激动剂使年老的生长锥的行为恢复活力，使它们重新受到netrin-1的吸引，而拮抗剂使年轻的生长锥被排斥。这些发现表明，netrin-1的反应性是发育调节的，并表明cAMP水平降低的内在变化是这种调节的基础。
Retinal axons are led out of the eye by netrin-1, an attractive guidance cue which is secreted at the optic nerve head. In the optic pathway, however, netrin-1 is expressed in areas that exclude retinal axon growth. This suggests that axons may change in their responsiveness to netrin-1 as they advance along the pathway. Indeed, in our 'whole-pathway' preparation in Xenopus, a gradual change from attraction to repulsion occurred as retinal axons emerged from progressively distal points along the pathway. We also found that axons that were aged in culture without pathway experience underwent a similar change, which correlated with a decline in cyclic AMP (cAMP) and netrin-1 receptor expression. Cyclic AMP elevators and adenosine A2b receptor agonists rejuvenated the behavior of old growth cones, causing them to regain attraction to netrin-1, whereas antagonists caused young growth cones to be repelled. These findings show that netrin-1 responsiveness is developmentally regulated and suggest that intrinsic changes that lower cAMP levels underlie this regulation.