Robust neuronal symmetry breaking by Ras-triggered local positive feedback
Robust neuronal symmetry breaking by Ras-triggered local positive feedback
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DOI：
10.1016/j.cub.2007.11.051
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发表时间：
2008-01-08
期刊：
影响因子：
9.2
通讯作者：
Meyer, Tobias
中科院分区：
文献类型：
--
作者：
Fivaz, Marc;Bandara, Samuel;Meyer, Tobias
神经元极性是由对称性破坏事件引发的，其中多个小神经突中的一个经历快速生长并成为轴突[1]。轴突形成受到磷脂酰肌醇 3 激酶 (PI3K) 相关信号元件 [2-10] 的调节，这些信号元件驱动局部肌动蛋白 [11] 和微管重组 [3, 12]，但导致对称性破坏并保证单个轴突形成的上游信号通路尚不清楚。在这里，我们在海马神经元中使用实时 FRET 成像，结果表明，小 GTPase HRas（PI3K 的上游调节因子）的活性在对称性破坏时在新生轴突生长锥中显着增加。 HRas 活性的这种局部增加是由 HRas 和 PI3K 之间的正反馈回路引起的，并且通过 HRas 向轴突生长锥的囊泡运输而局部得到加强。 HRas 向轴突生长锥的募集与剩余神经突中 HRas 浓度的降低同时发生，这表明对有限 HRas 库的竞争保证了只有一个轴突形成。数学模型表明，HRas 和 PI3K 之间的局部正反馈，再加上有限的 HRas 池的招募，在没有外在空间线索的情况下，会产生强大的对称性破坏和单个轴突的形成。
Neuronal polarity is initiated by a symmetry-breaking event whereby one out of multiple minor neurites undergoes rapid outgrowth and becomes the axon [1]. Axon formation is regulated by phosphatidylinositol 3-kinase (PI3K)-related signaling elements [2-10] that drive local actin [11] and microtubule reorganization [3, 12], but the upstream signaling circuit that causes symmetry breaking and guarantees the formation of a single axon is not known. Here, we use live FRET imaging in hippocampal neurons and show that the activity of the small GTPase HRas, an upstream regulator of PI3K, markedly increases in the nascent axonal growth cone upon symmetry breaking. This local increase in HRas activity results from a positive feedback loop between HRas and PI3K, locally reinforced by vesicular transport of HRas to the axonal growth cone. Recruitment of HRas to the axonal growth cone is paralleled by a decrease in HRas concentration in the remaining neurites, suggesting that competition for a limited pool of HRas guarantees that only one axon forms. Mathematical modeling demonstrates that local positive feedback between HRas and PI3K, coupled to recruitment of a limited pool of HRas, generates robust symmetry breaking and formation of a single axon in the absence of extrinsic spatial cues.