Lipid raft-targeted Akt promotes axonal branching and growth cone expansion via mTOR and Rac1, respectively.
Lipid raft-targeted Akt promotes axonal branching and growth cone expansion via mTOR and Rac1, respectively.
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DOI：
10.1002/jnr.22140
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发表时间：
2009-11-01
影响因子：
4.2
通讯作者：
Shine HD
中科院分区：
文献类型：
--
作者：
Grider MH;Park D;Spencer DM;Shine HD
细胞外引导信号调节轴突形态的分子机制还不完全清楚。最近的研究结果表明，蛋白激酶Akt的活性增加，促进海马神经元树突的分支和延伸。我们测试了在初级感觉神经元中组成型活性Akt（CA-Akt）的表达是否会促进轴突分支，以及是否将CA-Akt靶向脂筏（Akt功能的常见位点）会差异调节轴突形态。感觉神经元的生物枪转导诱导CA-Akt的快速表达，导致轴突分支增加、细胞肥大和生长锥扩张。此外，我们发现，与整个神经元中CA-Akt的表达相比，CA-Akt靶向脂筏显著增强生长锥扩张。由于脂筏集中在生长锥内，这一发现表明扩张的信号可能是局部调节的。我们发现，CA-Akt介导的生长锥扩张（但不是轴突分支）会因显性负性Rac 1的共表达而减弱。与此相反，阻断哺乳动物雷帕霉素靶蛋白（mTOR）阻止了CA-Akt引起的轴突分支和肥大，但没有阻止生长锥扩张。这些数据表明，Akt活性可以通过局部Rac 1信号传导调节生长锥扩张，并通过激活mTOR调节轴突分支和索马大小。
The molecular mechanisms by which extracellular guidance cues regulate axonal morphology are not fully understood. Recent findings suggest that increased activity of the protein kinase Akt promotes dendritic branching and elongation in hippocampal neurons. We tested whether expression of constitutively active Akt (CA-Akt) in primary sensory neurons would promote axonal branching and whether targeting CA-Akt to lipid rafts, common sites of Akt function, would differentially regulate axonal morphology. Biolistic transduction of sensory neurons induced a rapid expression of CA-Akt, resulting in increased axonal branching, cell hypertrophy, and growth cone expansion. Additionally, we found that targeting of CA-Akt to lipid rafts significantly potentiated growth cone expansion compared with expression of CA-Akt throughout the neuron. Because lipid rafts are concentrated within the growth cone, this finding suggests that signaling of expansion is likely regulated locally. We found that CA-Akt-mediated growth cone expansion, but not axonal branching, was attenuated by coexpression of dominant-negative Rac1. In contrast, blockade of mammalian target of rapamycin (mTOR) prevented axonal branching and hypertrophy in response to CA-Akt, but not growth cone expansion. These data indicate that Akt activity can regulate growth cone expansion via localized Rac1 signaling and regulate axonal branching and soma size via activation of mTOR.
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影响因子：
5.3
作者：
Dent, EW;Barnes, AM;Kalil, K
通讯作者：
Kalil, K
DOI：
10.1016/j.bbrc.2004.11.151
发表时间：
2005-02-04
影响因子：
3.1
作者：
Fujitani, M;Honda, A;Yamashita, T
通讯作者：
Yamashita, T
影响因子：
2.7
作者：
Kato, H;Chen, S;Taga, T
通讯作者：
Taga, T
影响因子：
3
作者：
Klimaschewski, L;Nindl, W;Pfaller, K
通讯作者：
Pfaller, K
影响因子：
16.2
作者：
Guirland, C;Suzuki, S;Zheng, JQ
通讯作者：
Zheng, JQ