https://ror.org/00pd74e08 Institut für Integrative Zellbiologie und Physiologie, Universität Münster, Münster, Germany.
https://ror.org/00pd74e08 Cells-in-Motion Interfaculty Center, University of Münster, Münster, Germany.
Life Sci Alliance. 2024 Mar 4;7(5). doi: 10.26508/lsa.202302383. Print 2024 May.
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)P). 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)P-dependent membrane properties limit the activity of C3G and Rap1 to ensure the extension of a single axon.
在分化过程中，神经元通过形成轴突和树突来建立高度极化的形态。皮质和海马神经元最初会延伸出几个短的突起，这些突起都有可能成为轴突。然后，通过促进轴突形成和防止其余突起发育成轴突的正反馈和负反馈信号的组合，选择其中一个突起作为轴突。在这里，我们表明，Pip5k1γ 作为一种负反馈信号，通过生成磷脂酰肌醇-4,5-二磷酸（PI(4,5)P）来调节 C3G 和 Rap1，从而需要形成单个轴突。破坏 Pip5k1γ 的功能会导致 Fyn/C3G/Rap1 途径过度激活，从而诱导形成多余的轴突。应用高渗冲击来调节膜张力也会产生类似的效果，增加 Rap1 活性并诱导形成多余的轴突。在这两种情况下，通过表达组成型激活的 Pip5k 都可以逆转多余轴突的诱导。我们的结果表明，PI(4,5)P 依赖性膜特性限制了 C3G 和 Rap1 的活性，以确保单个轴突的延伸。
