EphA4-dependent axon guidance is mediated by the RacGAP alpha2-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 alpha2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. alpha-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 alpha-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.
Wegmeyer
Heike
H
Department of Molecular Neurobiology and DFG Center for Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany.
Egea
Joaquim
J
Rabe
Nadine
N
Gezelius
Henrik
H
Filosa
Alessandro
A
Enjin
Anders
A
Varoqueaux
Frederique
F
Deininger
Katrin
K
Schnütgen
Frank
F
Brose
Nils
N
Klein
Rüdiger
R
Kullander
Klas
K
Betz
Andrea
A
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism*; D020848:Chimerin 1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D020233:Gait Disorders, Neurologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding / Q000235:genetics; D011712:Pyramidal Tracts / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D036122:Receptor, EphA4 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000002:abnormalities / Q000166:cytology / Q000378:metabolism