c-fos regulates neuronal excitability and survival
c-fos regulates neuronal excitability and survival
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DOI：
10.1038/ng859
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发表时间：
2002-04-01
期刊：
影响因子：
30.8
通讯作者：
Xu, M
中科院分区：
文献类型：
--
作者：
Zhang, JH;Zhang, DS;Xu, M
兴奋性毒性是谷氨酸或其他兴奋性氨基酸诱导神经元细胞死亡的过程。越来越多的证据表明，兴奋性毒性可能导致中枢神经系统急性损伤和慢性变性引起的人类神经元细胞损失（1-4）。即早基因（IEG）c-fos编码转录因子（5-6）。c-Fos蛋白与Jun家族蛋白形成异二聚体，所得AP-1复合物通过与许多细胞基因中发现的AP-1序列结合来调节转录（7-9）。新出现的证据表明，c-fos在调节神经元细胞存活与死亡方面至关重要（10）。尽管c-fos是由神经元活动诱导的，包括红藻氨酸诱导的癫痫发作（11-14），但c-fos是否以及如何参与兴奋性毒性仍然是未知的。为了解决这个问题，我们产生了一种小鼠，其中c-fos表达在海马中被大部分消除。我们发现，这些突变小鼠有更严重的红藻氨酸诱导的癫痫发作，增加神经元兴奋性和神经元细胞死亡，与对照组小鼠相比。此外，c-Fos调节红藻氨酸受体GluR 6和脑源性神经营养因子（BDNF）的表达，在体内和体外。我们的研究结果表明，c-fos是一个遗传调节细胞机制介导神经元的兴奋性和生存。
Excitotoxicity is a process in which glutamate or other excitatory amino acids induce neuronal cell death. Accumulating evidence suggests that excitotoxicity may contribute to human neuronal cell loss caused by acute insults and chronic degeneration in the central nervous system(1-4). The immediate early gene (IEG) c-fos encodes a transcription factor(5-6). The c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes(7-9). Emerging evidence suggests that c-fos is essential in regulating neuronal cell survival versus death(10). Although c-fos is induced by neuronal activity, including kainic acid induced seizures(11-14), whether and how c-fos is involved in excitotoxicity is still unknown. To address this issue, we generated a mouse in which c-fos expression is largely eliminated in the hippocampus. We found that these mutant mice have more severe kainic acid-induced seizures, increased neuronal excitability and neuronal cell death, compared with control mice. Moreover, c-Fos regulates the expression of the kainic acid receptor GluR6 and brain-derived neurotrophic factor (BDNF), both in vivo and in vitro. Our results suggest that c-fos is a genetic regulator for cellular mechanisms mediating neuronal excitability and survival.