Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling.

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

Cell

journal_title

Cell

authors

Iwasato T,Katoh H,Nishimaru H,Ishikawa Y,Inoue H,Saito YM,Ando R,Iwama M,Takahashi R,Negishi M,Itohara S

doi

10.1016/j.cell.2007.07.022

subject

Has Abstract

pub_date

2007-08-24 00:00:00

pages

742-53

issue

4

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(07)00959-2

journal_volume

130

pub_type

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