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Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during
R S Freeman1, S Estus, E M Johnson
1Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Saint Louis, Missouri 63110.
Abstract:
Sympathetic neurons undergo RNA and protein synthesis-dependent programmed cell death when deprived of nerve growth factor. To test the hypothesis that neuronal programmed cell death is a consequence of conflicting growth signals which cause the inappropriate activation of cell cycle genes, we have analyzed cell cycle-related genes for their expression in postmitotic neurons. Surprisingly, many of these genes are expressed in neurons, although cdc2, cdk2, and cyclin A are not. During programmed cell death, the expression of most of these genes, including several cyclins and the Rb and p53 tumor suppressor genes, decreases similar to that of neuronal genes. In contrast, cyclin D1 expression is selectively induced in dying neurons. Cyclin D1 mRNA levels peak 15-20 hr after nerve growth factor withdrawal, concurrent with the time that neurons become committed to die. These results provide an extensive characterization of cell cycle gene expression in postmitotic neurons and provide the evidence for a gene induced during neuronal programmed cell death.
Insights
Nerve growth factor withdrawal triggers programmed cell death in sympathetic neurons. This study reveals cyclin D1 is induced during this process, suggesting a role for cell cycle genes in neuronal death.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Sympathetic neurons undergo programmed cell death (PCD) when deprived of nerve growth factor (NGF).
- The role of cell cycle gene expression in postmitotic neuronal PCD is not fully understood.
- Conflicting growth signals may inappropriately activate cell cycle genes, leading to neuronal death.
Purpose of the Study:
- To investigate the expression of cell cycle-related genes in postmitotic neurons.
- To determine if cell cycle gene expression changes during NGF withdrawal-induced PCD.
- To identify specific cell cycle genes involved in neuronal apoptosis.
Main Methods:
- Analysis of cell cycle gene expression in postmitotic sympathetic neurons.
- Quantitative assessment of gene expression levels via mRNA analysis.
- Correlation of gene expression changes with the timing of neuronal commitment to die.
Main Results:
- Many cell cycle genes are expressed in postmitotic neurons, but cdc2, cdk2, and cyclin A are absent.
- During PCD, expression of most cell cycle genes, including Rb and p53 tumor suppressors, decreases.
- Cyclin D1 expression is selectively induced in dying neurons, with mRNA levels peaking around 15-20 hours post-NGF withdrawal.
Conclusions:
- Neuronal PCD involves complex regulation of cell cycle gene expression.
- Cyclin D1 is a key gene induced during NGF withdrawal-induced sympathetic neuron apoptosis.
- These findings suggest a potential role for cell cycle regulators in neuronal survival and death pathways.