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The Journal of Neuroscience, March 15, 2003, 23(6):2112
Ischemic Insults Derepress the Gene Silencer REST in Neurons
Destined to Die
Agata
Calderone,
Teresa
Jover*,
Kyung-min
Noh*,
Hidenobu
Tanaka ,
Hidenori
Yokota,
Ying
Lin,
Sonja Y.
Grooms,
Roodland
Regis,
Michael
V. L.
Bennett, and
R. Suzanne
Zukin
Department of Neuroscience, Albert Einstein College of Medicine,
Bronx, New York 10461
A subset of genes implicated in genetic and acquired neurological
disorders encode proteins essential to neural patterning and
neurogenesis. The gene silencing transcription factor neuronal repressor element-1 silencing transcription factor
(REST)/neuron-restrictive silencer factor (NRSF) plays a
critical role in elaboration of the neuronal phenotype. In neural
progenitor and non-neural cells, REST acts by repression of a subset of
neural genes important to synaptic plasticity and synaptic remodeling,
including the AMPA receptor (AMPAR) subunit GluR2. Here we show that
global ischemia triggers REST mRNA and protein expression. REST
suppresses GluR2 promoter activity and gene expression in neurons
destined to die. Because the GluR2 subunit governs AMPAR
Ca2+ permeability, these changes are expected to
have profound effects on neuronal survival. In keeping with this
concept, acute knockdown of the REST gene by antisense administration
prevents GluR2 suppression and rescues post-ischemic neurons from
ischemia-induced cell death in an in vitro model. To our
knowledge, our study represents the first example of ischemia-induced
induction of a master transcriptional regulator gene and its protein
expression critical to neural differentiation and patterning in adult
neurons. Derepression of REST is likely to be an important mechanism of
insult-induced neuronal death.
Key words:
REST; chromatin remodeling; transcription factors; AMPA receptors; neuronal insult; neuronal death; global ischemia; hippocampus
*
T.J. and K.N. contributed equally to this work.
Deceased, Oct. 13, 2002. We remember and honor Hidenobu
Tanaka for his scientific insight, creativity, technical acumen and his
warmth and sensitivity as a human being.
Copyright © 2003 Society for Neuroscience 0270-6474/03/2362112-10$05.00/0
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