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Copyright © 2003 by the Society for Neuroscience.
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
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
The editors suggest the following Related Resources on Science sites:In Science Signaling
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