PIP3 is involved in neuronal polarization and axon formation
PIP3 is involved in neuronal polarization and axon formation
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DOI：
10.1046/j.1471-4159.2004.02302.x
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发表时间：
2004-04-01
影响因子：
4.7
通讯作者：
Kaibuchi, K
中科院分区：
文献类型：
--
作者：
Ménager, C;Arimura, N;Kaibuchi, K
最近在哺乳动物中性粒细胞和盘状变形虫等多种细胞类型中的实验表明，pi3 -激酶的脂质产物PIP3在决定内部极性方面起着关键作用。在神经元中，由于一个神经突的伸长，轴突被指定，细胞获得极性。为了验证PI 3-激酶和PIP3可能在神经元极性，特别是轴突规范中发挥作用的假设，我们观察了Akt-PH-GFP在发育中的海马神经元中PIP3的定位。我们发现PIP3在生长过程的尖端积累。这种积累可以通过添加PI 3-激酶抑制剂来抑制。这些抑制剂与PIP3在过程形成和伸长中的作用一致，延迟了从1期神经元到3期神经元的转变，以及轴突的形成和伸长。此外，当未成熟的神经突接触涂有层粘连蛋白（一种已知可诱导轴突特异性的底物）的珠粒时，PIP3在其生长锥中积累，随后神经突迅速伸长。在这种情况下，添加PI 3-激酶抑制剂抑制PIP3积累和未来轴突伸长。这些结果表明，PIP3可能通过刺激神经突生长参与轴突的形成。此外，当第二个神经突与小珠接触时，这个神经突迅速伸长，而第一个与层粘连蛋白接触的神经突的伸长停止，这与从生长的未来轴突到其他神经突的负反馈机制的假设一致。
Recent experiments in various cell types such as mammalian neutrophils and Dictyostelium discoideum amoebae point to a key role for the lipid product of PI 3-kinase, PIP3, in determining internal polarity. In neurons, as a consequence of the elongation of one neurite, the axon is specified and the cell acquires its polarity. To test the hypothesis that PI 3-kinase and PIP3 may play a role in neuronal polarity, and especially in axon specification, we observed localization of PIP3 visualized by Akt-PH-GFP in developing hippocampal neurons. We found that PIP3 accumulates in the tip of the growing processes. This accumulation is inhibited by addition of PI 3-kinase inhibitors. Those inhibitors, consistently with a role of PIP3 in process formation and elongation, delay the transition from stage 1 neurons to stage 3 neurons, and both axon formation and elongation. Moreover, when the immature neurite contacts a bead coated with laminin, a substrate known to induce axon specification, PIP3 accumulates in its growth cone followed by a rapid elongation of the neurite. In such conditions, the addition of PI 3-kinase inhibitors inhibits both PIP3 accumulation and future axon elongation. These results suggest that PIP3 is involved in axon specification, possibly by stimulating neurite outgrowth. In addition, when a second neurite contacted the beads, this neurite rapidly elongates whereas the elongation of the first laminin-contacting neurite stops, consistently with the hypothesis of a negative feedback mechanism from the growing future axon to the other neurites.