A novel Dbl family RhoGEF promotes Rho-dependent axon attraction to the central nervous system midline in Drosophila and overcomes Robo repulsion
A novel Dbl family RhoGEF promotes Rho-dependent axon attraction to the central nervous system midline in Drosophila and overcomes Robo repulsion
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DOI：
10.1083/jcb.200110077
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发表时间：
2001-12-24
影响因子：
7.8
通讯作者：
Goodman, CS
中科院分区：
文献类型：
--
作者：
Bashaw, GJ;Hu, HL;Goodman, CS
Rho家族GTP酶Rac、Rho和CDC 42在调节肌动蛋白细胞骨架中的kev作用已被充分确立（Hall，A. 1998.科学279：509-514）。越来越多的证据表明Rho GTP酶及其上游正调节因子鸟嘌呤核苷酸交换因子（GEF）在发育中的神经系统中生长锥导向的控制中也起重要作用（Luo，L. 2000.国家神经科学院1：173-180; Dickson，B.J.2001. Curr. Opin. Neurobiol. 11：103-110）。在这里，我们提出了一个新的Dbl家庭Rho GEF，GEF 64 C，促进轴突吸引到胚胎果蝇神经系统的中枢神经系统中线的识别和分子特征。在致敏的遗传背景下，GEF 64 C功能的丧失会导致轴突穿过中线太少的表型。相比之下，GEF 64 C在整个神经系统中的异位表达导致其中太多的轴突穿过中线的表型，这是一种让人想起Roundabout（Robo）排斥性引导受体中的功能突变丧失的表型。遗传分析表明，GEF 64 C的表达实际上可以克服Robo排斥。令人惊讶的是，来自遗传、生物化学和细胞培养实验的证据表明，GEF 64 C促进轴突吸引依赖于Rho的激活，而不是Rac或Cdc 42。
The kev role of the Rho family GTPases Rac, Rho, and CDC42 in regulating the actin cytoskeleton is well established (Hall, A. 1998. Science. 279:509-514). Increasing evidence suggests that the Rho GTPases and their upstream positive regulators, guanine nucleotide exchange factors (GEFs), also play important roles in the control of growth cone guidance in the developing nervous system (Luo, L. 2000. Nat. Rev. Neurosci. 1:173-180; Dickson, B.J. 2001. Curr. Opin. Neurobiol. 11:103-110). Here, we present the identification and molecular characterization of a novel Dbl family Rho GEF, GEF64C, that promotes axon attraction to the central nervous system midline in the embryonic Drosophila nervous system. In sensitized genetic backgrounds, loss of GEF64C function causes a phenotype where too few axons cross the midline. In contrast, ectopic expression of GEF64C throughout the nervous system results in a phenotype in which far too many axons cross the midline, a phenotype reminiscent of loss of function mutations in the Roundabout (Robo) repulsive guidance receptor. Genetic analysis indicates that GEF64C expression can in fact overcome Robo repulsion. Surprisingly, evidence from genetic, biochemical, and cell culture experiments suggests that the promotion of axon attraction by GEF64C is dependent on the activation of Rho, but not Rac or Cdc42.