Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China, and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
J Neurosci. 2014 Mar 26;34(13):4494-508. doi: 10.1523/JNEUROSCI.3647-13.2014.
Dendritic arborization is one of the key determinants of precise circuits for information processing in neurons. Unraveling the molecular mechanisms underlying dendrite morphogenesis is critical to understanding the establishment of neuronal connections. Here, using gain- and loss-of-function approaches, we defined the chromodomain protein and transcription corepressor chromodomain Y-like (CDYL) protein as a negative regulator of dendrite morphogenesis in rat/mouse hippocampal neurons both in vitro and in vivo. Overexpressing CDYL decreased, whereas knocking it down increased, the dendritic complexity of the primary cultured rat neurons. High-throughput DNA microarray screening identified a number of CDYL downstream target genes, including the brain-derived neurotrophic factor (BDNF). Knock-down of CDYL in neuronal cells led to increased expression of BDNF, which is primarily responsible for CDYL's effects on dendrite patterns. Mechanistically, CDYL interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), directly and recruits the H3K27 methyltransferase activity to the promoter region of the BDNF gene. In doing so, CDYL and EZH2 coordinately restrict dendrite morphogenesis in an interdependent manner. Finally, we found that neural activity increased dendritic complexity through degradation of CDYL protein to unleash its inhibition on BDNF. These results link, for the first time, the epigenetic regulators CDYL and EZH2 to dendrite morphogenesis and might shed new light on our understanding of the regulation of the neurodevelopment.
树突分支是神经元中信息处理精确回路的关键决定因素之一。揭示树突形态发生的分子机制对于理解神经元连接的建立至关重要。在这里，我们使用增益和缺失功能方法，定义了色域蛋白和转录核心抑制因子色域 Y 样蛋白（CDYL）作为大鼠/小鼠海马神经元体外和体内树突形态发生的负调节剂。过表达 CDYL 减少，而敲低则增加原代培养的大鼠神经元的树突复杂性。高通量 DNA 微阵列筛选鉴定出许多 CDYL 的下游靶基因，包括脑源性神经营养因子（BDNF）。在神经元细胞中敲低 CDYL 导致 BDNF 的表达增加，BDNF 主要负责 CDYL 对树突模式的影响。在机制上，CDYL 与 EZH2（多梳抑制复合物 2（PRC2）的催化亚基）直接相互作用，并将 H3K27 甲基转移酶活性募集到 BDNF 基因的启动子区域。这样，CDYL 和 EZH2 以相互依赖的方式协同限制树突形态发生。最后，我们发现神经活动通过降解 CDYL 蛋白来增加树突复杂性，从而释放其对 BDNF 的抑制作用。这些结果首次将表观遗传调节剂 CDYL 和 EZH2 与树突形态发生联系起来，并可能为我们理解神经发育的调控提供新的线索。
