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Title: Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism
Authors: Fu, Wing Yu
Chen, Yu
Sahin, Mustafa
Zhao, Xioaosu
Shi, Lei
Bikoff, Jay B.
Lai, Kwok On
Yung, Wingho
Fu, Amy K. Y.
Greenberg, Michael E.
Ip, Nancy Y.
Keywords: Cyclin-dependent kinase 5
Eph receptors
Rho GTPase
Actin cytoskeleton
Dendritic development
Synaptic plasticity
Issue Date: Jan-2007
Citation: Nature neuroscience, v. 10, no. 1, Jan, 2007, p. 67-76
Abstract: The development of dendritic spines is thought to be crucial for synaptic plasticity. Dendritic spines are retracted upon EphA4 activation, but the mechanisms that control this process are not well understood. Here we report an important role of Cdk5 in EphA4-dependent spine retraction. We find that blockade of Cdk5 activity inhibits ephrin-A1-triggered spine retraction and reduction of mEPSC frequency at hippocampal synapses. Activation of EphA4 results in the recruitment of Cdk5 to EphA4, leading to the tyrosine phosphorylation and activation of Cdk5. EphA4 and Cdk5 then enhance the activation of ephexin1, a GEF that regulates RhoA activation. We show that the association between EphA4 and ephexin1 is significantly reduced in Cdk5–/– brains and that Cdk5-dependent phosphorylation of ephexin1 is required for 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.
Rights: The published version is available at The DOI is 10.1038/nn1811
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