Abstract
Developmental and pathological death of neurons requires activation of a defined pathway of cell cycle proteins. However, it is unclear how this pathway is regulated and whether it is relevant in vivo. A screen for transcripts robustly induced in cultured neurons by DNA damage identified Sertad1, a Cdk4 (cyclin-dependent kinase 4) activator. Sertad1 is also induced in neurons by nerve growth factor (NGF) deprivation and Abeta (beta-amyloid). RNA interference-mediated downregulation of Sertad1 protects neurons in all three death models. Studies of NGF withdrawal indicate that Sertad1 is required to initiate the apoptotic cell cycle pathway since its knockdown blocks subsequent pathway events. Finally, we find that Sertad1 expression is required for developmental neuronal death in the cerebral cortex. Sertad1 thus appears to be essential for neuron death in trophic support deprivation in vitro and in vivo and in models of DNA damage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.
Publication types
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Comparative Study
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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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Apoptosis / genetics
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Cell Survival / genetics
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Cell Survival / physiology
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Cerebral Cortex / enzymology
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Cerebral Cortex / pathology
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Cerebral Cortex / physiology
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Cyclin-Dependent Kinase 4 / metabolism
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DNA Damage / genetics
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Enzyme Activation / genetics
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Gene Expression Regulation, Developmental / physiology
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Mice
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Neurons / enzymology
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Neurons / pathology*
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Neurons / physiology*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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PC12 Cells
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RNA Interference / physiology
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Rats
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Rats, Sprague-Dawley
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors
Substances
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Apoptosis Regulatory Proteins
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Nuclear Proteins
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Sertad1 protein, mouse
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Trans-Activators
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Transcription Factors
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Cyclin-Dependent Kinase 4