Forebrain-Specific Neuronal Inhibition of Nuclear Factor-κB Activity Leads to Loss of Neuroprotection
| Autor: | Barbara Kaltschmidt, Sylvie Mémet, Francesco M. Rossi, Delphine Ndiaye, Bertrand Goudeau, Christian Kaltschmidt, Alain Israël, Valérie Fridmacher, Julia Pfeiffer |
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| Rok vydání: | 2003 |
| Předmět: |
Genetically modified mouse
Transgene Green Fluorescent Proteins Neurotoxins Mice Transgenic In Vitro Techniques Biology Hippocampus Neuroprotection Mice Transactivation Prosencephalon NF-KappaB Inhibitor alpha Gene expression medicine Animals Humans Transgenes Enzyme Inhibitors Promoter Regions Genetic Transcription factor Genes Dominant Neurons Kainic Acid Cell Death General Neuroscience Neurodegeneration NF-kappa B medicine.disease Molecular biology Cell biology Luminescent Proteins Gene Expression Regulation Organ Specificity Calcium-Calmodulin-Dependent Protein Kinases Mutation Forebrain I-kappa B Proteins Calcium-Calmodulin-Dependent Protein Kinase Type 2 Brief Communications |
| Zdroj: | The Journal of Neuroscience. 23:9403-9408 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.23-28-09403.2003 |
| Popis: | The transcription factor Rel/nuclear factor (NF)-kappaB is known for its fundamental role in regulating immune and inflammatory responses. In the brain, constitutive NF-kappaB activity has been detected exclusively in neurons, and a large diversity of stimuli have been reported to induce NF-kappaB 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 kappaB-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-kappaB-dependent transcriptional response is abolished in the forebrain. Calcium-calmodulin-dependent kinase II alpha promoter-driven tetracycline transactivator was used for regulated expression of a transdominant negative mutant of inhibitor kappaBalpha (super-repressor) together with a green fluorescent protein tracer. Inhibition of expression of a kappaB-dependent lacZ transgene was shown in triple transgenic mice, which correlated with the loss of kappaB-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-kappaB-driven gene expression increases neurodegeneration. This might lead to the path for new treatments of neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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