Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism.
The development of dendritic spines is thought to be crucial for synaptic plasticity. Dendritic spines are retracted upon Eph receptor A4 (EphA4) activation, but the mechanisms that control this process are not well understood. Here we report an important function of cyclin-dependent kinase 5 (Cdk5) in EphA4-dependent spine retraction in mice. We found that blocking Cdk5 activity inhibits ephrin-A1-triggered spine retraction and reduction of mEPSC frequency at hippocampal synapses. The activation of EphA4 resulted in the recruitment of Cdk5 to EphA4, leading to the tyrosine phosphorylation and activation of Cdk5. EphA4 and Cdk5 then enhanced the activation of ephexin1, a guanine-nucleotide exchange factor that regulates activation of the small Rho GTPase RhoA. The association between EphA4 and ephexin1 was significantly reduced in Cdk5(-/-) brains and Cdk5-dependent phosphorylation of ephexin1 was required for the ephrin-A1-mediated regulation of spine density. These findings suggest that ephrin-A1 promotes EphA4-dependent spine retraction through the activation of Cdk5 and ephexin1, which in turn modulates actin cytoskeletal dynamics.
Fu
Wing-Yu
WY
Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Chen
Yu
Y
Sahin
Mustafa
M
Zhao
Xiao-Su
XS
Shi
Lei
L
Bikoff
Jay B
JB
Lai
Kwok-On
KO
Yung
Wing-Ho
WH
Fu
Amy K Y
AK
Greenberg
Michael E
ME
Ip
Nancy Y
NY
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000502:physiology*; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation; D036082:Receptor, EphA1 / Q000235:genetics / Q000378:metabolism; D036122:Receptor, EphA4 / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014443:Tyrosine / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D014443:Tyrosine; D036082:Receptor, EphA1; D036122:Receptor, EphA4; D051360:Cyclin-Dependent Kinase 5; D020742:rhoA GTP-Binding Protein