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The Journal of Neuroscience, March 1, 2000, 20(5):1694-1700
Estrogen-Induced Activation of the Mitogen-Activated
Protein Kinase Cascade in the Cerebral Cortex of Estrogen
Receptor- Knock-Out Mice
Meharvan
Singh1,
György
Sétáló Jr1, 3,
Xiaoping
Guan1,
Donald E.
Frail4, and
C. Dominique
Toran-Allerand1, 2
Departments of 1 Anatomy and Cell Biology, and Centers
for Neurobiology and Behavior and Reproductive Sciences, and
2 Neurology, Columbia University College of Physicians and
Surgeons, New York, New York 10032, 3 Department of
Biology, University Medical School of Pécs, Pécs H-7643,
Hungary, and 4 Womens Health Research Institute,
Wyeth-Ayerst Research, Radnor, Pennsylvania 19087
We have shown previously in the developing cerebral cortex that
estrogen elicits the rapid and sustained activation of multiple signaling proteins within the mitogen-activated protein (MAP) kinase
cascade, including B-Raf and extracellular signal-regulated kinase
(ERK). Using estrogen receptor (ER)- gene-disrupted (ERKO) mice, we addressed the role of ER- in mediating this action of estrogen in the brain. 17 -Estradiol increased B-Raf activity and MEK
(MAP kinase/ERK kinase)-dependent ERK phosphorylation in
cerebral cortical explants derived from both ERKO and their wild-type
littermates. The ERK response was stronger in ERKO-derived cultures
but, unlike that of wild-type cultures, was not blocked by the estrogen
receptor antagonist ICI 182,780. Surprisingly, both the ER-
selective ligand 16-iodo-17-estradiol and the ER- selective
ligand genistein failed to elicit ERK phosphorylation, suggesting that
a different mechanism or receptor may mediate estrogen-induced ERK
phosphorylation in the cerebral cortex. Interestingly, the
transcriptionally inactive stereoisomer 17-estradiol did elicit a
strong induction of ERK phosphorylation, which, together with the
inability of the ER-- and ER--selective ligands to elicit ERK
phosphorylation, and of ICI 182,780 to block the actions of estradiol
in ERKO cultures, supports the hypothesis that a novel,
estradiol-sensitive and ICI-insensitive estrogen receptor may mediate
17-estradiol-induced activation of ERK in the brain.
Key words:
estradiol; estrogen receptor; ERK; ERKO; signal
transduction; brain; cerebral cortex
Copyright © 2000 Society for Neuroscience 0270-6474/00/2051694-07$05.00/0
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