EphA4-Dependent Axon Guidance Is Mediated by the RacGAP α2-Chimaerin

• Neuronal network formation in the developing nervous system is dependent on the accurate navigation of nerve cell axons and dendrites, which is controlled by attractive and repulsive guidance cues. Ephrins and their cognate Eph receptors mediate many repulsive axonal guidance decisions by intercellular interactions resulting in growth cone collapse and axon retraction of the Eph-presenting neuron. We show that the Rac-specific GTPase-activating protein α2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. α-Chimaerin mutant mice display a phenotype similar to that of EphA4 mutant mice, including aberrant midline axon guidance and defective spinal cord central pattern generator activity. Our results reveal an α-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.

Nyckelord

Animals

Animals; Newborn

Brain/abnormalities/metabolism/physiopathology

Cell Communication/genetics

Cell Differentiation/*genetics

Cells; Cultured

Central Nervous System/*abnormalities/cytology/*metabolism

Chimerin 1/genetics/*metabolism

Down-Regulation/genetics

Gait Disorders; Neurologic/genetics/metabolism/physiopathology

Gene Expression Regulation; Developmental/genetics

Growth Cones/*metabolism/ultrastructure

Mice

Mice; Knockout

Neural Pathways/abnormalities/metabolism/physiopathology

Protein Binding/genetics

Pyramidal Tracts/abnormalities/metabolism/physiopathology

Receptor; EphA4/*metabolism

Signal Transduction/genetics

Spinal Cord/abnormalities/cytology/metabolism

MEDICINE

MEDICIN

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)