EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association, and dendritic spine morphology.
Specialized postsynaptic structures known as dendritic spines are the primary sites of glutamatergic innervation at synapses of the CNS. Previous studies have shown that spines rapidly remodel their actin cytoskeleton to modify their shape and this has been associated with changes in synaptic physiology. However, the receptors and signaling intermediates that restructure the actin network in spines are only beginning to be identified. We reported previously that the EphA4 receptor tyrosine kinase regulates spine morphology. However, the signaling pathways downstream of EphA4 that induce spine retraction on ephrin ligand binding remain poorly understood. Here, we demonstrate that ephrin stimulation of EphA4 leads to the recruitment and activation of phospholipase Cgamma1 (PLCgamma1) in heterologous cells and in hippocampal slices. This interaction occurs through an Src homology 2 domain of PLCgamma1 and requires the EphA4 juxtamembrane tyrosines. In the brain, PLCgamma1 is found in multiple compartments of synaptosomes and is readily found in postsynaptic density fractions. Consistent with this, PLC activity is required for the maintenance of spine morphology and ephrin-induced spine retraction. Remarkably, EphA4 and PLC activity modulate the association of the actin depolymerizing/severing factor cofilin with the plasma membrane. Because cofilin has been implicated previously in the structural plasticity of spines, this signaling may enable cofilin to depolymerize actin filaments and restructure spines at sites of ephrin-EphA4 contact.
Zhou
Lei
L
Center for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada H3G 1A4.
Martinez
Sarah J
SJ
Haber
Michael
M
Jones
Emma V
EV
Bouvier
David
D
Doucet
Guy
G
Corera
Amadou T
AT
Fon
Edward A
EA
Zisch
Andreas H
AH
Murai
Keith K
KK
D008841:Actin Cytoskeleton / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D048430:Cell Shape / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000502:physiology; D036342:Ephrins / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D051966:Phospholipase C gamma / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D036122:Receptor, EphA4 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure
D051339:Actin Depolymerizing Factors; D036342:Ephrins; D036122:Receptor, EphA4; D051966:Phospholipase C gamma