Liang Zhuoyi, Ye Tao, Zhou Xiaopu, Lai Kwok-On, Fu Amy K Y, Ip Nancy Y
Division of Life Science, Molecular Neuroscience Center, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Division of Life Science, Molecular Neuroscience Center, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
J Neurosci. 2015 Nov 11;35(45):15127-34. doi: 10.1523/JNEUROSCI.1443-15.2015.
The proper growth and arborization of dendrites in response to sensory experience are essential for neural connectivity and information processing in the brain. Although neuronal activity is important for sculpting dendrite morphology, the underlying molecular mechanisms are not well understood. Here, we report that cyclin-dependent kinase 5 (Cdk5)-mediated transcriptional regulation is a key mechanism that controls activity-dependent dendrite development in cultured rat neurons. During membrane depolarization, Cdk5 accumulates in the nucleus to regulate the expression of a subset of genes, including that of the neurotrophin brain-derived neurotrophic factor, for subsequent dendritic growth. Furthermore, Cdk5 function is mediated through the phosphorylation of methyl-CpG-binding protein 2, a key transcriptional repressor that is mutated in the mental disorder Rett syndrome. These findings collectively suggest that the nuclear import of Cdk5 is crucial for activity-dependent dendrite development by regulating neuronal gene transcription during neural development.
Neural activity directs dendrite development through the regulation of gene transcription. However, how molecular signals link extracellular stimuli to the transcriptional program in the nucleus remains unclear. Here, we demonstrate that neuronal activity stimulates the translocation of the kinase Cdk5 from the cytoplasmic compartment into the nucleus; furthermore, the nuclear localization of Cdk5 is required for dendrite development in cultured neurons. Genome-wide transcriptome analysis shows that Cdk5 deficiency specifically disrupts activity-dependent gene transcription of bdnf. The action of Cdk5 is mediated through the modulation of the transcriptional repressor methyl-CpG-binding protein 2. Therefore, this study elucidates the role of nuclear Cdk5 in the regulation of activity-dependent gene transcription and dendritic growth.
树突根据感觉经验进行适当的生长和分支对于大脑中的神经连接和信息处理至关重要。虽然神经元活动对于塑造树突形态很重要，但其潜在的分子机制尚不清楚。在这里，我们报告细胞周期蛋白依赖性激酶5（Cdk5）介导的转录调控是控制培养的大鼠神经元中活动依赖性树突发育的关键机制。在膜去极化过程中，Cdk5在细胞核中积累，以调节包括神经营养因子脑源性神经营养因子在内的一组基因的表达，从而促进随后的树突生长。此外，Cdk5的功能是通过甲基-CpG结合蛋白2的磷酸化介导的，甲基-CpG结合蛋白2是一种关键的转录抑制因子，在精神疾病雷特综合征中发生突变。这些发现共同表明，Cdk5的核输入对于神经发育过程中通过调节神经元基因转录的活动依赖性树突发育至关重要。
神经活动通过基因转录的调控来指导树突发育。然而，分子信号如何将细胞外刺激与细胞核中的转录程序联系起来仍不清楚。在这里，我们证明神经元活动刺激激酶Cdk5从细胞质区室转运到细胞核中；此外，Cdk5的核定位是培养神经元中树突发育所必需的。全基因组转录组分析表明，Cdk5缺乏特异性破坏了脑源性神经营养因子的活动依赖性基因转录。Cdk5的作用是通过调节转录抑制因子甲基-CpG结合蛋白2来介导的。因此，本研究阐明了核Cdk5在调节活动依赖性基因转录和树突生长中的作用。
