Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction
Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction
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DOI：
10.1074/jbc.m116.744169
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发表时间：
2016-09-23
影响因子：
4.8
通讯作者：
Kundu, Tapas K.
中科院分区：
文献类型：
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作者：
Swaminathan, Amrutha;Delage, Helene;Kundu, Tapas K.
虽然组蛋白和非组蛋白蛋白复合物的精心组合定义了染色质组织，因此调节了许多核过程，染色质组织蛋白的作用在生物体水平上仍然未被探索。高度丰富，多功能，染色质相关蛋白和转录辅激活因子阳性辅激活因子4（PC 4/Sub1）是绝对重要的生命，因为它的缺乏导致胚胎致死。在这里，我们报告了条件性PC 4敲除（PC 4（f/f）Nestin-Cre）小鼠的结果，其中PC 4在大脑中被特异性敲除。与对照（PC 4（+/+）Nestin-Cre）小鼠相比，PC 4（f/f）Nestin-Cre小鼠较小，夜间活动减少，但可生育，并且未显示运动功能障碍。这些小鼠大脑不同区域的神经元显示出对缺氧/缺氧的敏感性，并且在齿状回中观察到成年神经发生减少。有趣的是，PC 4（f/f）Nestin-Cre小鼠在空间记忆消退方面表现出严重缺陷，而获得和长期保持不受影响。PC 4（f/f）Nestin-Cre小鼠背海马的基因表达分析显示，几个神经功能相关基因的表达失调，PC 4始终被发现定位于这些基因的启动子上，表明PC 4调节它们的表达。这些观察结果表明，非组蛋白染色质相关蛋白，如PC 4在神经元可塑性中起着重要作用。
Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain. Compared with the control (PC4(+/+) Nestin-Cre) mice, PC4(f/f) Nestin-Cre mice are smaller with decreased nocturnal activity but are fertile and show no motor dysfunction. Neurons in different areas of the brains of these mice show sensitivity to hypoxia/anoxia, and decreased adult neurogenesis was observed in the dentate gyrus. Interestingly, PC4(f/f) Nestin-Cre mice exhibit a severe deficit in spatial memory extinction, whereas acquisition and long term retention were unaffected. Gene expression analysis of the dorsal hippocampus of PC4(f/f) Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression. These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity.