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The Journal of Neuroscience, March 1, 2003, 23(5):1649

The E2F-Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons

Yoshiyuki Konishi and Azad Bonni

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Neuronal apoptosis plays a critical role in the normal development of the mammalian brain and is thought to contribute to the pathogenesis of several neurologic disorders. However, the intracellular mechanisms underlying apoptosis of neurons remain incompletely understood. In the present study, we characterized a cell-cycle-based mechanism by which neuronal activity deprivation induces apoptosis of postmitotic neurons. Activity deprivation, but not growth factor withdrawal, was found to induce Cdc2 expression and consequent Cdc2-mediated apoptosis in granule neurons of the developing rat cerebellum. We found that activity deprivation induces cdc2 transcription in neurons via an E2F-binding element (EBE) within the cdc2 promoter. The transcription factor E2F1 that is expressed in granule neurons was found in DNA binding assays to bind to the EBE of the cdc2 gene. In chromatin immunoprecipitation analysis, endogenous E2F1 forms a complex with the promoter of the endogenous cdc2 gene in granule neurons, indicating that endogenous E2F1 is poised to activate transcription of the endogenous cdc2 gene in neurons. Consistent with this conclusion, a dominant interfering form of E2F, when expressed in granule neurons, blocked activity deprivation-induced cdc2 transcription. In other experiments, we found that the expression of E2F1 in granule neurons induces Cdc2 expression and promotes neuronal apoptosis via the activation of Cdc2. Remarkably, in contrast to inducing the E2F-mediated expression and activation of Cdc2 in granule neurons, activity deprivation fails to stimulate the expression of E2F-target genes that trigger DNA synthesis and replication. Together, our findings define a novel apoptotic mechanism whereby E2F selectively couples an activity deprivation-induced signal to cdc2 transcription in the absence of stimulating DNA synthesis and thus culminating in Cdc2-mediated apoptosis of postmitotic neurons.

Key words: Cdc2; E2F; apoptosis; neuron; activity; transcription; cell cycle; promoter

Copyright © 2003 Society for Neuroscience  0270-6474/03/2351649-10$05.00/0

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