[HTML][HTML] Rac-GAP α-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling

T Iwasato, H Katoh, H Nishimaru, Y Ishikawa, H Inoue… - Cell, 2007 - cell.com
T Iwasato, H Katoh, H Nishimaru, Y Ishikawa, H Inoue, YM Saito, R Ando, M Iwama…
Cell, 2007cell.com
The ephrin/Eph system plays a central role in neuronal circuit formation; however, its
downstream effectors are poorly understood. Here we show that α-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 …
Summary
The ephrin/Eph system plays a central role in neuronal circuit formation; however, its downstream effectors are poorly understood. Here we show that α-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 α-chimerin leads to mfy phenotypes similar to those of EphA4−/− and ephrinB3−/− mice. α-chimerin interacts with EphA4 and, in response to ephrinB3/EphA4 signaling, inactivates Rac, which is a positive regulator of process outgrowth. Moreover, downregulation of α-chimerin suppresses ephrinB3-induced growth cone collapse in cultured neurons. Our findings indicate that ephrinB3/EphA4 signaling prevents growth cone extension in motor circuit formation via α-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.
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