Asymmetric PI(3,4,5)P3 and Akt signaling mediates chemotaxis of axonal growth cones.
Asymmetric PI(3,4,5)P3 and Akt signaling mediates chemotaxis of axonal growth cones.
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DOI：
10.1523/jneurosci.0216-11.2011
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发表时间：
2011-05-11
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影响因子：
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通讯作者：
Henley JR
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文献类型：
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作者：
Henle SJ;Wang G;Liang E;Wu M;Poo MM;Henley JR
许多细胞外引导信号在轴突寻路中的作用需要生长锥上的Ca2+内流，但是引导信号受体的激活如何导致质乳离子通道的打开仍然很大程度上未知。与变形虫细胞的趋化性类似，我们发现，通过在非洲爪蟾脊髓神经元中gfp标记的Akt结合域的易位，趋化剂的梯度触发生长锥边缘快速的不对称PI(3,4,5)P3积累。生长锥的化学吸引需要PI(3,4,5)P3的产生和Akt的激活，在体外和体内，极化Akt活性的遗传扰动破坏了轴突寻路。此外，来自生长锥的膜片钳记录显示，外源PI(3,4,5)P3快速激活TRP（瞬时受体电位）通道，不对称施加PI(3,4,5)P3足以诱导化学吸引的生长锥转向，这种方式需要下游Ca2+信号。因此，不对称PI(3,4,5)P3升高和Akt激活是生长锥趋化性的早期事件，将受体激活与TRP通道打开和Ca2+信号传导联系起来。综上所述，我们的研究结果表明，PI(3,4,5)P3高度偏光到生长锥的前沿，可以在趋化引导过程中起到早期调节作用。
The action of many extracellular guidance cues on axon pathfinding requires Ca2+ influx at the growth cone, but how activation of guidance cue receptors leads to opening of plasmalemmal ion channels remains largely unknown. Analogous to the chemotaxis of amoeboid cells, we found that a gradient of chemoattractant triggered rapid asymmetric PI(3,4,5)P3 accumulation at the growth cone’s leading edge, as detected by the translocation of a GFP-tagged binding domain of Akt in Xenopus laevis spinal neurons. Growth cone chemoattraction required PI(3,4,5)P3 production and Akt activation, and genetic perturbation of polarized Akt activity disrupted axon pathfinding in vitro and in vivo. Furthermore, patch-clamp recording from growth cones revealed that exogenous PI(3,4,5)P3 rapidly activated TRP (transient receptor potential) channels, and asymmetrically applied PI(3,4,5)P3 was sufficient to induce chemoattractive growth cone turning in a manner that required downstream Ca2+ signaling. Thus, asymmetric PI(3,4,5)P3 elevation and Akt activation are early events in growth cone chemotaxis that link receptor activation to TRP channel opening and Ca2+ signaling. Altogether, our findings reveal that PI(3,4,5)P3 elevation polarizes to the growth cone’s leading edge and can serve as an early regulator during chemotactic guidance.