Li Ang, Zhu Hui-Ming, Chen Yu, Yan Fang, Liu Zhong-Ying, Li Zhen-Lin, Dong Wei-Ren, Zhang Lin, Wang Hai-Hong
Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Experimental Education & Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Cell Mol Neurobiol. 2021 Oct;41(7):1599-1610. doi: 10.1007/s10571-021-01051-0. Epub 2021 Feb 11.
The establishment of polarity is an essential process in early neuronal development. Cdc42, a GTPase of the Rho family, is a key regulator of cytoskeletal dynamics and neuronal polarity. However, the mechanisms underlying the action of cdc42 in regulating axonogenesis have not been elucidated. Here, we expressed wild-type cdc42, a constitutively active cdc42 mutant (cdc42F28L) and a dominant negative cdc42 mutant (cdc42N17), respectively, in the primary hippocampal neurons to alter the activity of cdc42. We found that cdc42 activities were paralleled with the capacities to promote axonogenesis in the cultured neurons. Cdc42 also enhanced microtubule stability in the cultured neurons. Pharmacologically stabilizing microtubules significantly abrogated the defective axonogenesis induced by cdc42 inhibition. Moreover, cdc42 promoted the dephosphorylation of collapsing response mediator protein-2 (CRMP-2) at Thr514 by increasing GSK-3β phosphorylation at Ser9 in the cultured neurons. These findings suggest that cdc42 may facilitate axonogenesis by promoting microtubule stabilization in rat primary hippocampal neurons.
极性的建立是早期神经元发育的一个重要过程。Cdc42是Rho家族的一种GTP酶，是细胞骨架动力学和神经元极性的关键调节因子。然而，Cdc42在调节轴突发生中的作用机制尚未阐明。在这里，我们分别在原代海马神经元中表达野生型Cdc42、组成型活性Cdc42突变体（Cdc42F28L）和显性负性Cdc42突变体（Cdc42N17），以改变Cdc42的活性。我们发现Cdc42的活性与培养神经元中促进轴突发生的能力平行。Cdc42还增强了培养神经元中微管的稳定性。药理学上稳定微管显著消除了由Cdc42抑制诱导的轴突发生缺陷。此外，Cdc42通过增加培养神经元中Ser9位点的GSK-3β磷酸化促进了塌陷反应调节蛋白-2（CRMP-2）在Thr514位点的去磷酸化。这些发现表明，Cdc42可能通过促进大鼠原代海马神经元中的微管稳定来促进轴突发生。
