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Distinct functions of Trio GEF domains in axon outgrowth of cerebellar granule neurons.
Journal of Genetics and Genomics ( IF 5.9 ) Pub Date : 2019-02-23 , DOI: 10.1016/j.jgg.2019.02.003
Tao Tao 1 , Jie Sun 1 , Yajing Peng 1 , Pei Wang 1 , Xin Chen 1 , Wei Zhao 1 , Yeqiong Li 1 , Lisha Wei 1 , Wei Wang 1 , Yanyan Zheng 1 , Ye Wang 1 , Xuena Zhang 1 , Min-Sheng Zhu 1
Affiliation  

As a critical guanine nucleotide exchange factor (GEF) regulating neurite outgrowth, Trio coordinates multiple processes of cytoskeletal dynamics through activating Rac1, Cdc42 and RhoA small GTPases by two GEF domains, but the in vivo roles of these GEF domains and corresponding downstream effectors have not been determined yet. We established multiple lines of knockout mice and assessed the respective roles of Trio GEF domains and Rac1 in axon outgrowth. Knockout of total Trio in cerebellar granule neurons (CGNs) led to an impaired F-actin rearrangement of growth cone and hence a retarded neurite outgrowth. Such a retardation was reproduced by inhibition of GEF1 domain or knockdown of Cdc42 and restored apparently by introduction of active Cdc42. As Rac1 deficiency did not affect the neurite outgrowth of CGNs, we suggested that Trio GEF1-mediated Cdc42 activation was required for neurite outgrowth. We established a GEF2-knockout line with deletion of all Trio isoforms except a cerebella-specific Trio8, a short isoform of Trio without GEF2 domain, and used this line as a GEF2-deficient animal model. The GEF2-deficient CGNs had a normal neurite outgrowth but abolished Netrin-1-promoted growth, without affecting Netrin-1 induced Rac1 activation. We thus suggested that Trio GEF1-mediated Cdc42 activation rather than Rac1 activation drives the F-actin dynamics necessary for neurite outgrowth, while GEF2 functions in Netrin-1-promoted neurite elongation. Our results delineated the distinct roles of Trio GEF domains in neurite outgrowth, which is instructive to understand the pathogenesis of clinical Trio-related neurodevelopmental disorders.



中文翻译:

Trio GEF域在小脑颗粒神经元轴突生长中的不同功能。

作为调节神经突向外生长的关键鸟嘌呤核苷酸交换因子(GEF),三重通过由两个结构域GEF激活的Rac1,Cdc42和RhoA的小GTP酶坐标细胞骨架动力学的多个进程,但在体内这些GEF结构域和相应的下游效应子的作用尚未确定。我们建立了多个基因敲除小鼠品系,并评估了Trio GEF域和Rac1在轴突生长中的各自作用。小脑颗粒神经元(CGNs)中总三重基因的敲除导致生长锥的F-肌动蛋白重排受损,并因此延缓了神经突的长出。这种抑制作用是通过抑制GEF1结构域或敲低Cdc42来再现的,并且显然是通过引入活性Cdc42来恢复的。由于Rac1缺乏并不影响CGN的神经突生长,因此我们建议Trio GEF1介导的Cdc42激活对于神经突生长是必需的。我们建立了一条GEF2-敲除品系,其中除小脑特异性Trio8(一种没有GEF2域的Trio的短同种型)外,所有Trio亚型都缺失了,并将这条线用作缺乏GEF2的动物模型。缺乏GEF2的CGN具有正常的神经突增生,但废除了Netrin-1促进的生长,而不影响Netrin-1诱导的Rac1激活。因此,我们建议Trio GEF1介导的Cdc42激活而不是Rac1激活驱动神经突生长所需的F-肌动蛋白动力学,而GEF2在Netrin-1促进的神经突伸长中起作用。我们的研究结果描述了Trio GEF域在神经突增生中的独特作用,这对于理解临床Trio相关神经发育障碍的发病机理具有指导意义。因此,我们建议Trio GEF1介导的Cdc42激活而不是Rac1激活驱动神经突生长所需的F-肌动蛋白动力学,而GEF2在Netrin-1促进的神经突伸长中起作用。我们的研究结果描述了Trio GEF域在神经突增生中的独特作用,这对于理解临床Trio相关神经发育障碍的发病机理具有指导意义。因此,我们建议Trio GEF1介导的Cdc42激活而不是Rac1激活驱动神经突生长所需的F-肌动蛋白动力学,而GEF2在Netrin-1促进的神经突伸长中起作用。我们的研究结果描述了Trio GEF域在神经突增生中的独特作用,这对于理解临床Trio相关神经发育障碍的发病机理具有指导意义。

更新日期:2019-02-23
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