Forebrain-Specific Neuronal Inhibition of Nuclear Factor-κB Activity Leads to Loss of Neuroprotection
Forebrain-Specific Neuronal Inhibition of Nuclear Factor-κB Activity Leads to Loss of Neuroprotection
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前脑特异性神经元抑制核因子-κB 活性导致神经保护丧失
DOI：
10.1523/jneurosci.23-28-09403.2003
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
S. Mémet
中科院分区：
文献类型：
--
作者：
V. Fridmacher;B. Kaltschmidt;B. Goudeau;Delphine Ndiaye;F. M. Rossi;J. Pfeiffer;C. Kaltschmidt;A. Israël;S. Mémet
已知转录因子Rel/核因子（NF）-κB在调节免疫和炎症反应中的基本作用。在脑中，仅在神经元中检测到组成型NF-κB活性，并且已经报道了大量不同的刺激物诱导NF-κB活性。然而，这种转录因子在神经系统中的功能仍不清楚，其在神经保护或神经退行性变中的作用也存在争议。最近的研究表明，神经元中κ B驱动的基因表达受Sp1样因子的调控。为了澄清这种争议，我们在这里描述了一种新的小鼠模型，其中整个NF-κ B依赖性转录反应在前脑中被消除。钙-钙调蛋白依赖性激酶II α启动子驱动的四环素反式激活因子与绿色荧光蛋白示踪剂一起用于调节抑制剂κBα（超阻遏物）的反式显性负突变体的表达。在三重转基因小鼠中显示了κ B依赖性lacZ转基因表达的抑制，这与κ B特异性DNA结合的丧失相关。在转基因器官型海马脑片培养中，超阻遏物的表达导致神经毒性损伤后的强烈细胞死亡。这些数据首次表明，NF-κ B驱动的基因表达的神经元限制性消融增加了神经变性。这可能为神经退行性疾病的新治疗开辟道路。
The transcription factor Rel/nuclear factor (NF)-κB is known for its fundamental role in regulating immune and inflammatory responses. In the brain, constitutive NF-κB activity has been detected exclusively in neurons, and a large diversity of stimuli have been reported to induce NF-κB activity. Yet the function of this transcription factor in the nervous system remains unclear, and its role in neuroprotection or neurodegeneration is open to debate. Recently it was suggested that κB-driven gene expression in neurons is controlled by Sp1-like factors. To clarify such controversy, we have characterized here a novel mouse model in which the entire NF-κB-dependent transcriptional response is abolished in the forebrain. Calcium-calmodulin-dependent kinase II α promoter-driven tetracycline transactivator was used for regulated expression of a transdominant negative mutant of inhibitor κBα (super-repressor) together with a green fluorescent protein tracer. Inhibition of expression of a κB-dependent lacZ transgene was shown in triple transgenic mice, which correlated with the loss of κB-specific DNA binding. In transgenic organotypic hippocampal slice cultures, expression of the super-repressor led to strong cell death after neurotoxic insults. These data demonstrate for the first time that neuron-restricted ablation of NF-κB-driven gene expression increases neurodegeneration. This might lead to the path for new treatments of neurodegenerative diseases.
DOI：
10.1073/pnas.94.8.4103
发表时间：
1997-04-15
影响因子：
11.1
作者：
Schauwecker, PE;Steward, O
通讯作者：
Steward, O