During their differentiation, neurons establish a highly polarized morphology by forming axons and dendrites. Cortical and hippocampal neurons initially extend several short neurites that all have the potential to become an axon. One of these neurites is then selected as the axon by a combination of positive and negative feedback signals that promote axon formation and prevent the remaining neurites from developing into axons. Here, we show that Pip5k1γ is required for the formation of a single axon as a negative feedback signal that regulates C3G and Rap1 through the generation of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂). Impairing the function of Pip5k1γ results in a hyper-activation of the Fyn/C3G/Rap1 pathway, which induces the formation of supernumerary axons. Application of a hyper-osmotic shock to modulate membrane tension has a similar effect, increasing Rap1 activity and inducing the formation of supernumerary axons. In both cases, the induction of supernumerary axons can be reverted by expressing constitutively active Pip5k. Our results show that PI(4,5)P₂-dependent membrane properties limit the activity of C3G and Rap1 to ensure the extension of a single axon.

中文翻译：

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Pip5k1γ 通过限制 Rap1 活性来调节轴突形成。

在分化过程中，神经元通过形成轴突和树突建立高度极化的形态。皮质和海马神经元最初延伸出几个短神经突，这些短神经突都有可能成为轴突。然后，通过正反馈信号和负反馈信号的组合，选择这些神经突之一作为轴突，促进轴突形成并防止剩余的神经突发育成轴突。在这里，我们表明 Pip5k1γ 是单个轴突形成所必需的，作为负反馈信号，通过生成磷脂酰肌醇-4,5-二磷酸 (PI(4,5)P ₂ ) 来调节 C3G 和 Rap1。损害 Pip5k1γ 的功能会导致 Fyn/C3G/Rap1 通路过度激活，从而诱导多余轴突的形成。应用高渗休克来调节膜张力也有类似的效果，增加 Rap1 活性并诱导多余轴突的形成。在这两种情况下，多余轴突的诱导可以通过表达组成型活性 Pip5k 来恢复。我们的结果表明，PI(4,5)P ₂依赖的膜特性限制了C3G和Rap1的活性，以确保单个轴突的延伸。