Abstract:
: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.
journal_name
Celljournal_title
Cellauthors
Iwasato T,Katoh H,Nishimaru H,Ishikawa Y,Inoue H,Saito YM,Ando R,Iwama M,Takahashi R,Negishi M,Itohara Sdoi
10.1016/j.cell.2007.07.022subject
Has Abstractpub_date
2007-08-24 00:00:00pages
742-53issue
4eissn
0092-8674issn
1097-4172pii
S0092-8674(07)00959-2journal_volume
130pub_type
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