Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons.
Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons.
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DOI：
10.1371/journal.pbio.0050063
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发表时间：
2007-04
期刊：
影响因子：
9.8
通讯作者：
Ip, Nancy Y
中科院分区：
文献类型：
--
作者：
Cheung, Zelda H;Chin, Wing Hong;Chen, Yu;Ng, Yu Pong;Ip, Nancy Y
神经营养因子是神经发育过程中神经元存活和分化的关键调节因子。它们的同源受体Trk受体是一类受体酪氨酸激酶(RTK)，在调节神经营养因子的下游功能中起着关键作用。最近的研究表明，细胞周期蛋白依赖性激酶5(CDK5)是一种丝氨酸/苏氨酸激酶，可能通过其受体的磷酸化来调节RTK信号。鉴于CDK5和Trk受体在神经系统中的丰富表达，以及它们相互参与神经元结构和突触功能的调节，研究CDK5是否也可能调节Trk信号是有意义的。在目前的研究中，我们报告了TrkB作为CDK5底物的鉴定。CDK5在TrkB的胞内膜旁区域的Ser478处磷酸化TrkB。有趣的是，缺乏CDK5磷酸化位点的TrkB突变体的CDK5活性减弱或过表达本质上取消了脑源性神经营养因子(BDNF)诱导的原代海马神经元的树突状生长。此外，我们还发现，CDK5参与了BDNF诱导的Rho GTP酶CDc42的激活，而Rho GTPase CDc42是BDNF触发的树突生长所必需的。因此，我们的观察揭示了CDK5在TrkB通过调节BDNF诱导的CDC42激活而调节树突状细胞生长中的意外作用。神经系统中信息的准确传输需要神经元之间精确形成接触点。对这些接触部位的调节涉及微调神经元上树突的数量和分支。在整个发育过程中，有几个分泌因子调节树突数量和分支。这些因子中的一个重要家族是神经营养因子，它们对神经元的生存和发育是不可或缺的。例如，用一种神经营养因子脑源性神经营养因子(BDNF)刺激海马神经元，会增加直接从细胞体延伸出来的树突的数量。在这里，我们报告了BDNF刺激的树突状细胞生长需要BDNF受体TrkB被一种被称为细胞周期蛋白依赖性激酶5(CDK5)的激酶磷酸化。通过抑制CDK5对TrkB的磷酸化，基本上消除了BDNF对树突的诱导。我们的观察表明，CDK5是神经营养素功能的调节因子。由于CDK5和神经营养因子都在神经元发育中发挥重要作用，我们的研究结果表明，CDK5和TrkB之间的相互作用可能也参与了发育过程中其他生物学过程的调节。由脑源性神经营养因子(BDNF)刺激的树突状细胞生长需要BDNF受体TrkB被一种被称为细胞周期蛋白依赖性激酶5(CDK5)的激酶磷酸化。本研究发现了CDK5和TrkB之间的一种新的相互作用。
Neurotrophins are key regulators of neuronal survival and differentiation during development. Activation of their cognate receptors, Trk receptors, a family of receptor tyrosine kinases (RTKs), is pivotal for mediating the downstream functions of neurotrophins. Recent studies reveal that cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase, may modulate RTK signaling through phosphorylation of the receptor. Given the abundant expression of both Cdk5 and Trk receptors in the nervous system, and their mutual involvement in the regulation of neuronal architecture and synaptic functions, it is of interest to investigate if Cdk5 may also modulate Trk signaling. In the current study, we report the identification of TrkB as a Cdk5 substrate. Cdk5 phosphorylates TrkB at Ser478 at the intracellular juxtamembrane region of TrkB. Interestingly, attenuation of Cdk5 activity or overexpression of a TrkB mutant lacking the Cdk5 phosphorylation site essentially abolishes brain-derived neurotrophic factor (BDNF)–triggered dendritic growth in primary hippocampal neurons. In addition, we found that Cdk5 is involved in BDNF-induced activation of Rho GTPase Cdc42, which is essential for BDNF-triggered dendritic growth. Our observations therefore reveal an unanticipated role of Cdk5 in TrkB-mediated regulation of dendritic growth through modulation of BDNF-induced Cdc42 activation. Accurate transmission of information in the nervous system requires the precise formation of contact points between neurons. Regulation of these contact sites involves fine tuning the number and branching of dendritic processes on neurons. Throughout development, several secreted factors act to regulate dendrite number and branching. One important family of these factors is neurotrophins, which are indispensable for the survival and development of neurons. For example, stimulation of hippocampal neurons with one neurotrophin, brain-derived neurotrophic factor (BDNF), increases the number of dendrites directly extending from the cell body. Here, we report that BDNF-stimulated dendritic growth requires phosphorylation of the BDNF receptor, TrkB, by a kinase known as cyclin-dependent kinase 5 (Cdk5). Inhibiting phosphorylation of TrkB by Cdk5 essentially abolishes the induction of dendrites by BDNF. Our observations reveal that Cdk5 serves as a regulator of neurotrophin function. Since Cdk5 and neurotrophins both play essential roles in neuronal development, our findings suggest that the interplay between Cdk5 and TrkB may also be implicated in the regulation of other biological processes during development. Dendritic growth stimulated by brain-derived neurotrophic factor (BDNF) requires phosphorylation of the BDNF receptor, TrkB, by a kinase known as cyclin-dependent kinase 5 (Cdk5). This study identifies a novel interplay between Cdk5 and TrkB.