Mediator Med23 Regulates Adult Hippocampal Neurogenesis
Mediator Med23 Regulates Adult Hippocampal Neurogenesis
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Med23 调节成人海马神经发生
DOI：
10.3389/fcell.2020.00699
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发表时间：
2020-07-29
影响因子：
5.5
通讯作者：
Su, Chang-Jun
中科院分区：
文献类型：
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作者：
Chen, Guo-Yan;Zhang, Shuai;Su, Chang-Jun
哺乳动物介导子（Mammalian Mediator，Med）是基因表达的关键调控因子，通过连接转录因子和RNA聚合酶II（PolII）转录机制来调控基因表达。Mediator亚基23（Med 23）是保守的Med蛋白复合物的成员，并且在包括脂肪形成、癌发生、成骨细胞分化和T细胞活化的多种生物学过程中发挥重要作用。然而，它在神经系统中的潜在功能仍然未知。我们在这里报告，Med 23是必需的成年小鼠海马神经发生。在Nestin-CreER：Med 23 flox/flox小鼠中，通过口服他莫昔芬实现成体海马神经干细胞（NSC）中Med 23的缺失。我们发现，通过脉冲BrdU标记和MCM 2和Ki 67的免疫染色显示，增殖的NSC数量增加，这可能是由于细胞周期长度缩短，GFAP+/Sox 2 + NSC和Tbr 2+祖细胞未发生变化。另一方面，在Med 23缺陷小鼠的齿状回（DG）中，NeuroD和DCX指示的成神经细胞和未成熟神经元的数量减少。此外，这些小鼠还表现出有缺陷的树突形态发生，以及空间和背景恐惧记忆的缺陷。基因本体（GO）分析显示，海马神经干细胞的增殖、Pol II相关转录、Notch信号通路和凋亡相关基因丰富。这些结果表明，Med 23在调节成人脑神经发生和功能中起作用。
Mammalian Mediator (Med) is a key regulator of gene expression by linking transcription factors to RNA polymerase II (Pol II) transcription machineries. The Mediator subunit 23 (Med23) is a member of the conserved Med protein complex and plays essential roles in diverse biological processes including adipogenesis, carcinogenesis, osteoblast differentiation, and T-cell activation. However, its potential functions in the nervous system remain unknown. We report here that Med23 is required for adult hippocampal neurogenesis in mouse. Deletion of Med23 in adult hippocampal neural stem cells (NSCs) was achieved in Nestin-CreER:Med23flox/flox mice by oral administration of tamoxifen. We found an increased number of proliferating NSCs shown by pulse BrdU-labeling and immunostaining of MCM2 and Ki67, which is possibly due to a reduction in cell cycle length, with unchanged GFAP+/Sox2+ NSCs and Tbr2+ progenitors. On the other hand, neuroblasts and immature neurons indicated by NeuroD and DCX were decreased in number in the dentate gyrus (DG) of Med23-deficient mice. In addition, these mice also displayed defective dendritic morphogenesis, as well as a deficiency in spatial and contextual fear memory. Gene ontology (GO) analysis of hippocampal NSCs revealed an enrichment in genes involved in cell proliferation, Pol II-associated transcription, Notch signaling pathway and apoptosis. These results demonstrate that Med23 plays roles in regulating adult brain neurogenesis and functions.