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βPix-d 通过 PAK/Stathmin1 信号通路促进微管乙酰化和神经突生长。

βPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway.

机构信息

School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.

Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.

出版信息

PLoS One. 2020 Apr 6;15(4):e0230814. doi: 10.1371/journal.pone.0230814. eCollection 2020.

Abstract

Microtubules are a major cytoskeletal component of neurites, and the regulation of microtubule stability is essential for neurite morphogenesis. βPix (ARHGEF7) is a guanine nucleotide exchange factor for the small GTPases Rac1 and Cdc42, which modulate the organization of actin filaments and microtubules. βPix is expressed as alternatively spliced variants, including the ubiquitous isoform βPix-a and the neuronal isoforms βPix-b and βPix-d, but the function of the neuronal isoforms remains unclear. Here, we reveal the novel role of βPix neuronal isoforms in regulating tubulin acetylation and neurite outgrowth. At DIV4, hippocampal neurons cultured from βPix neuronal isoform knockout (βPix-NIKO) mice exhibit defects in neurite morphology and tubulin acetylation, a type of tubulin modification which often labels stable microtubules. Treating βPix-NIKO neurons with paclitaxel, which stabilizes the microtubules, or reintroducing either neuronal βPix isoform to the KO neurons overcomes the impairment in neurite morphology and tubulin acetylation, suggesting that neuronal βPix isoforms may promote microtubule stabilization during neurite development. βPix-NIKO neurons also exhibit lower phosphorylation levels for Stathmin1, a microtubule-destabilizing protein, at Ser16. Expressing either βPix neuronal isoform in the βPix-NIKO neurons restores Stathmin1 phosphorylation levels, with βPix-d having a greater effect than βPix-b. Furthermore, we find that the recovery of neurite length and Stathmin1 phosphorylation via βPix-d expression requires PAK kinase activity. Taken together, our study demonstrates that βPix-d regulates the phosphorylation of Stathmin1 in a PAK-dependent manner and that neuronal βPix isoforms promote tubulin acetylation and neurite morphogenesis during neuronal development.

摘要

微管是神经突的主要细胞骨架成分,微管稳定性的调节对于神经突形态发生至关重要。βPix(ARHGEF7)是小 GTP 酶 Rac1 和 Cdc42 的鸟嘌呤核苷酸交换因子,调节肌动蛋白丝和微管的组织。βPix 表达为可变剪接变体,包括普遍存在的同种型βPix-a 和神经元同种型βPix-b 和βPix-d,但神经元同种型的功能仍不清楚。在这里,我们揭示了βPix 神经元同种型在调节微管乙酰化和神经突生长中的新作用。在 DIV4,培养来自βPix 神经元同种型敲除(βPix-NIKO)小鼠的海马神经元表现出神经突形态和微管乙酰化缺陷,微管乙酰化是一种经常标记稳定微管的微管修饰类型。用紫杉醇处理βPix-NIKO 神经元,紫杉醇稳定微管,或向 KO 神经元重新引入任何一种神经元βPix 同种型,都可以克服神经突形态和微管乙酰化的损伤,这表明神经元βPix 同种型可能在神经突发育过程中促进微管稳定。βPix-NIKO 神经元还表现出微管不稳定蛋白 Stathmin1 的 Ser16 磷酸化水平较低。在βPix-NIKO 神经元中表达任何一种βPix 神经元同种型都可以恢复 Stathmin1 的磷酸化水平,βPix-d 的效果比βPix-b 更大。此外,我们发现通过βPix-d 表达恢复神经突长度和 Stathmin1 磷酸化需要 PAK 激酶活性。总之,我们的研究表明,βPix-d 通过 PAK 依赖性方式调节 Stathmin1 的磷酸化,神经元βPix 同种型在神经元发育过程中促进微管乙酰化和神经突形态发生。

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