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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Involvement of a Rac activator,P-Rex1, in neurotrophin-derived signaling and neuronal migration.
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Involvement of a Rac activator,P-Rex1, in neurotrophin-derived signaling and neuronal migration.

机译：Rac激活剂P-Rex1参与神经营养蛋白衍生的信号传导和神经元迁移。

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摘要

Rho-family GTPases play key roles in regulating cytoskeletal reorganization, contributing to many aspects of nervous system development. Their activities are known to be regulated by guanine nucleotide exchange factors (GEFs), in response to various extracellular cues. P-Rex1, a GEF for Rac, has been mainly investigated in neutrophils, in which this molecule contributes to reactive oxygen species formation. However, its role in the nervous system is essentially unknown. Here we describe the expression profile and a physiological function of P-Rex1 in nervous system development. In situ hybridization revealed that P-Rex1 is dynamically expressed in a variety of cells in the developing mouse brain, including some cortical and DRG neurons. In migrating neurons in the intermediate zone, P-Rex1 protein was found to localize in the leading process and adjacent cytoplasmic region. When transfected in pheochromocytoma PC12 cells, P-Rex1 can be activated by NGF, causing an increase in GTP-bound Rac1 and cell motility. Deletion analyses suggested roles for distinct domains of this molecule. Experiments using a P-Rex1 mutant lacking the Dbl-homology domain, a dominant-negative-like form, and small interfering RNA showed that endogenous P-Rex1 was involved in cell migration of PC12 cells and primary cultured neurons from the embryonic day 14 cerebral cortices, induced by extracellular stimuli (NGF, BDNF, and epidermal growth factor). Furthermore, in utero electroporation of the mutant protein into the embryonic cerebral cortex perturbed radial neuronal migration. These findings suggest that P-Rex1, which is expressed in a variety of cell types, is activated by extracellular cues such as neurotrophins and contributes to neuronal migration in the developing nervous system.
机译：Rho家族GTPases在调节细胞骨架重组中起关键作用，在神经系统发育的许多方面做出了贡献。已知它们的活性受鸟嘌呤核苷酸交换因子（GEF）的调节，以响应各种细胞外信号。 P-Rex1是Rac的GEF，主要在嗜中性粒细胞中进行了研究，其中该分子有助于形成活性氧。但是，其在神经系统中的作用基本上是未知的。在这里，我们描述了P-Rex1在神经系统发育中的表达谱和生理功能。原位杂交表明，P-Rex1在发育中的小鼠大脑中的各种细胞中动态表达，包括一些皮质和DRG神经元。在中间区域迁移的神经元中，发现P-Rex1蛋白位于前导过程和邻近的细胞质区域。当在嗜铬细胞瘤PC12细胞中转染时，P-Rex1可以被NGF激活，从而导致结合GTP的Rac1和细胞运动性增加。缺失分析提示了该分子不同域的作用。使用缺乏Dbl同源结构域，显性负性样形式和小干扰RNA的P-Rex1突变体进行的实验表明，内源性P-Rex1参与了PC12细胞和来自胚胎第14天大脑的原代培养神经元的细胞迁移皮质，由细胞外刺激（NGF，BDNF和表皮生长因子）诱导。此外，在子宫内，突变蛋白进入胚胎脑皮质的电穿孔扰动了放射状神经元迁移。这些发现表明，在多种细胞类型中表达的P-Rex1被诸如神经营养蛋白等细胞外信号激活，并促进了神经系统发育中的神经元迁移。

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