Status epilepticus induced Gadd45b is required for augmented dentate neurogenesis
Status epilepticus induced Gadd45b is required for augmented dentate neurogenesis
复制标题
癫痫持续状态诱导的 Gadd45b 是增强齿状神经发生所必需的
DOI：
10.1016/j.scr.2020.102102
复制
发表时间：
2020
影响因子：
1.2
通讯作者：
Jian-Xin Liu
中科院分区：
文献类型：
--
作者：
Xin-Li Xiao;Xiao-Lin Wu;Peng-Bo Yang;Hai-Bo Hu;Yu Chen;Min Li;Kai-Wei Si;Feng Wu;Jian-Xin Liu
在颞叶癫痫（TLE）动物模型中，癫痫持续状态（SE）导致齿状回亚颗粒带（SGZ）新生神经元数量急剧增加。SE如何在齿状神经发生中起调节作用尚不清楚。Gadd45b通过DNA去甲基化参与表观遗传基因激活。本研究旨在揭示硒诱导齿状神经发生的新机制。在匹罗卡品诱导SE小鼠齿状回中观察到Gadd45b的短暂诱导（12小时至3天）。用BrdU标记分裂细胞后，我们发现在SE后7天和14天，需要诱导Gadd45b来提高齿状回细胞的增殖率。随后，使用Sequenom MassARRAY分析仪检测对成人神经发生至关重要的候选生长因子基因的DNA甲基化水平。结果表明，Gadd45b是se诱导的齿状回特定启动子DNA去甲基化和相应基因表达所必需的，包括脑源性神经营养因子（BDNF）和成纤维细胞生长因子-2 （FGF-2）。通过Timm染色，我们进一步发现SE诱导的Gadd45b可能通过对SE后早期齿状神经发生的表观遗传调控参与了慢性癫痫海马随后的苔藓纤维发芽（MFS）。总之，Gadd45b将匹罗卡品诱导的SE与齿状回分泌因子的表观遗传DNA修饰联系起来，从而导致神经发生的外源性调节。
In animal models with temporal lobe epilepsy (TLE), the status epilepticus (SE) leads to a dramatic increase in number of newly born neuron in the subgranular zone (SGZ) of dentate gyrus. How the SE confers a modulation in the dentate neurogenesis is mostly unknown. Gadd45b is involved in epigenetic gene activation by DNA demethylation. This study was performed to present a novel mechanism underling SE-induced dentate neurogenesis. A transient induction (12 hrs to 3 days) of Gadd45b was observed in dentate gyrus of mice after pilocarpine-induced SE. Labeling the dividing cells with BrdU, we next found that the induction of Gadd45b was required to increase the rate of cell proliferation in the dentate gyrus at 7 and 14 days after SE. Afterward, the DNA methylation levels for candidate growth factor genes critical for the adult neurogenesis were assayed with Sequenom MassARRAY Analyzer. The results indicated that Gadd45b was necessary for SE-induced DNA demethylation of specific promoters and expression of corresponding genes in the dentate gyrus, including brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF-2). Using Timm staining, we further suggested that SE-induced Gadd45b might contribute to the subsequent mossy fiber sprouting (MFS) in the chronically epileptic hippocampus via epigenetic regulation of dentate neurogenesis at early stage after SE. Together, Gadd45b links pilocarpine-induced SE to epigenetic DNA modification of secreted factors in the dentate gyrus, leading to extrinsic modulation on the neurogenesis.