Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling.
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 in motor 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.
Iwasato
Takuji
T
Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), 2-1 Hirosawa Wako-shi, Saitama 351-0198, Japan.
Katoh
Hironori
H
Nishimaru
Hiroshi
H
Ishikawa
Yukio
Y
Inoue
Haruhisa
H
Saito
Yoshikazu M
YM
Ando
Reiko
R
Iwama
Mizuho
M
Takahashi
Ryosuke
R
Negishi
Manabu
M
Itohara
Shigeyoshi
S
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D020848:Chimerin 1 / Q000378:metabolism*; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D036389:Ephrin-B3 / Q000235:genetics / Q000378:metabolism*; D005808:Genes, Recessive; D008040:Genetic Linkage; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000502:physiology*
D020848:Chimerin 1; D036389:Ephrin-B3; D012701:Serotonin; D016202:N-Methylaspartate; D020744:rac GTP-Binding Proteins