Rac-GAP α-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling
Rac-GAP α-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling
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DOI：
10.1016/j.cell.2007.07.022
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发表时间：
2007-08-24
期刊：
影响因子：
64.5
通讯作者：
Itohara, Shigeyoshi
中科院分区：
文献类型：
--
作者：
Iwasato, Takuji;Katoh, Hironori;Itohara, Shigeyoshi
Ephrin/Eph系统在神经元回路形成中起着核心作用;然而，对其下游效应子的了解甚少。在这里，我们表明，α-嵌合蛋白Rac GTP酶激活蛋白介导ephrinB 3/EphA 4正向信号。我们发现了一种自发的小鼠突变miffy（mfy），它会导致类似兔子的跳跃步态，受损的皮质脊髓轴突导向和异常的脊髓中枢模式发生器。使用定位克隆、转基因拯救和基因靶向，我们证明了α-嵌合蛋白的缺失导致与EphA 4（-/-）和ephrinB 3（-/-）小鼠相似的mfy表型。α-嵌合蛋白与EphA 4相互作用，并且响应于肝配蛋白B3/EphA 4信号传导，使Rac失活，Rac是过程生长的正调节剂。此外，下调α-嵌合蛋白抑制ephrinB 3诱导的生长锥崩溃在培养的神经元。我们的研究结果表明ephrinB 3/EphA 4信号通过α-嵌合蛋白诱导的Rac失活阻止了运动回路形成中的生长锥延伸。他们还强调了Rho家族GTP酶激活蛋白作为肝配蛋白/Eph信号传导的关键介体的作用。
The ephrin/Eph system plays a central role in neuronal circuit formation; however, its downstream effectors are poorly understood. Here we show that alpha-chimerin Rac GTPase-activating protein mediates ephrinB3/EphA4 forward signaling. We discovered a spontaneous mouse mutation, miffy ( mfy), which results in a rabbit-like hopping gait, impaired corticospinal axon guidance, and abnormal spinal central pattern generators. Using positional cloning, transgene rescue, and gene targeting, we demonstrated that loss of alpha-chimerin leads to mfy phenotypes similar to those of EphA4(-/-) and ephrinB3(-/-) mice. alpha-chimerin interacts with EphA4 and, in response to ephrinB3/EphA4 signaling, inactivates Rac, which is a positive regulator of process outgrowth. Moreover, downregulation of alpha-chimerin suppresses ephrinB3-induced growth cone collapse in cultured neurons. Our findings indicate that ephrinB3/EphA4 signaling prevents growth cone extension inmotor circuit formation via alpha-chimerin-induced inactivation of Rac. They also highlight the role of a Rho family GTPase-activating protein as a key mediator of ephrin/Eph signaling.