Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons
Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons
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DOI：
10.1101/gad.310204
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发表时间：
2004-09-01
影响因子：
10.5
通讯作者：
Samakovlis, C
中科院分区：
文献类型：
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作者：
Lundström, A;Gallio, M;Samakovlis, C
Slit蛋白通过与Robo受体结合来引导许多细胞类型的迁移，但Robo如何控制细胞运动尚不清楚。我们描述了vilse，果蝇基因所需的Robo排斥上皮细胞和轴突的功能分析。Vilse定义了一个保守的RhoGAP家族（Rho GTP酶激活蛋白），在果蝇和脊椎动物中具有代表性。vilse突变体的表型类似于CNS中线处的Slit和Robo突变体的气管和轴突表型。vilse，slit和robo突变体之间的剂量敏感性遗传相互作用表明，vilse是robo信号的一个组成部分。此外，Vilse在气管中的机器人突变体改善了机器人的表型，表明Vilse的行为下游的机器人介导中线排斥。Vilse和它的人类同源物直接结合到相应的Robo受体的细胞内结构域，并促进RacGTP的水解，并且不太有效地促进Cdc42GTP的水解。这些结果连同与机器人，Vilse，和RAC突变体的遗传相互作用实验表明，机器人排斥的机制，通过Vilse介导的本地化的灭活的RAC。
Slit proteins steer the migration of many cell types through their binding to Robo receptors, but how Robo controls cell motility is not clear. We describe the functional analysis of vilse, a Drosophila gene required for Robo repulsion in epithelial cells and axons. Vilse defines a conserved family of RhoGAPs (Rho GTPase-activating proteins), with representatives in flies and vertebrates. The phenotypes of vilse mutants resemble the tracheal and axonal phenotypes of Slit and Robo mutants at the CNS midline. Dosage-sensitive genetic interactions between vilse, slit, and robo mutants suggest that vilse is a component of robo signaling. Moreover, overexpression of Vilse in the trachea of robo mutants ameliorates the phenotypes of robo, indicating that Vilse acts downstream of Robo to mediate midline repulsion. Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP and, less efficiently, of Cdc42GTP. These results together with genetic interaction experiments with robo, vilse, and rac mutants suggest a mechanism whereby Robo repulsion is mediated by the localized inactivation of Rac through Vilse.