Abstract
Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1alpha independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Dose-Response Relationship, Drug
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism*
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Female
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Gene Expression Profiling
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Glutamic Acid / pharmacology
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hydrogen Peroxide / pharmacology
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Ionomycin / pharmacology
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Kainic Acid / pharmacology
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Male
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Mice
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Mice, Knockout
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Neurons / cytology
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Neurons / metabolism*
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Neuroprotective Agents / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
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Oxidants / pharmacology
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors
Substances
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Cyclic AMP Response Element-Binding Protein
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Neuroprotective Agents
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Nr4a2 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Oxidants
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Trans-Activators
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Transcription Factors
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Glutamic Acid
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Ionomycin
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Hydrogen Peroxide
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Kainic Acid