Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice

We have shown previously in the developing cerebral cortex that estrogen el icits the rapid and sustained activation of multiple signaling proteins wit hin the mitogen-activated protein (MAP) kinase cascade, including B-Raf and extracellular signal-regulated kinase (ERK). Using estrogen receptor (ER)- alpha gene-disrupted (ERKO) mice, we addressed the role of ER-alpha in medi ating this action of estrogen in the brain. 17 beta-Estradiol increased B-R af activity and MEK (MAP kinase/ERK kinase) dependent ERK phosphorylation i n cerebral cortical explants derived from both ERKO and their wild-type lit termates. The ERK response was stronger in ERKO-derived cultures but, unlik e that of wild-type cultures, was not blocked by the estrogen receptor anta gonist ICI 182,780. Surprisingly, both the ER-alpha selective ligand 16 alp ha-iodo-17 beta-estradiol and the ER-beta selective ligand genistein failed to elicit ERK phosphorylation, suggesting that a different mechanism or re ceptor may mediate estrogen-induced ERK phosphorylation in the cerebral cor tex. Interestingly, the transcriptionally inactive stereoisomer 17 alpha-es tradiol did elicit a strong induction of ERK phosphorylation, which, togeth er with the inability of the ER-alpha- and ER-beta-selective ligands to eli cit ERK phosphorylation, and of ICI 182,780 to block the actions of estradi ol in ERKO cultures, supports the hypothesis that a novel, estradiol-sensit ive and ICI-insensitive estrogen receptor may mediate 17 beta-estradiol-ind uced activation of ERK in the brain.