Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism
Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism
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DOI：
10.1038/nn1811
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发表时间：
2007-01-01
影响因子：
25
通讯作者：
Ip, Nancy Y.
中科院分区：
文献类型：
--
作者：
Fu, Wing-Yu;Chen, Yu;Ip, Nancy Y.
树突棘的发育被认为是突触可塑性的关键。树突棘在Eph受体A4(EphA4)激活时收缩，但控制这一过程的机制尚不清楚。在这里，我们报道了细胞周期蛋白依赖的激酶5(CDK5)在EphA4依赖的小鼠脊柱回缩中的重要作用。我们发现，阻断CDK5活性可以抑制ephin-A1触发的脊椎回缩和海马突触mEPSC频率的降低。EphA4的激活导致CDK5被募集到EphA4，导致酪氨酸磷酸化和CDK5的激活。然后，EphA4和CDK5增强了Ephexin1的激活，Ephexin1是一种鸟嘌呤核苷酸交换因子，调节小Rho GTP酶RhoA的激活。在CDK5(-/-)脑中，EphA4和Ephexin1之间的关联显著减少，并且EphA4和Ephexin1之间的联系需要依赖于CDK5的Ephexin1的磷酸化来调节ePhin-A1介导的脊柱密度。这些发现表明，ePhin-A1通过激活CDK5和Ephexin1促进EphA4依赖的脊柱回缩，进而调节肌动蛋白细胞骨架的动力学。
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.