Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: Convergence of estrogen and neurotrophin signaling pathways

We have shown that estrogen elicits a selective enhancement of the growth a nd differentiation of axons and dendrites (neurites) in the developing CNS. We subsequently demonstrated widespread colocalization of estrogen and neu rotrophin receptors (trk) within developing forebrain neurons and reciproca l transcriptional regulation of these receptors by their ligands. Using org anotypic explants of the cerebral cortex, we tested the hypothesis that est rogen/neurotrophin receptor coexpression also may result in convergence or cross-coupling of their signaling pathways. Estradiol elicited rapid (withi n 5-15 min) tyrosine phosphorylation/activa'tion of the mitogen-activated p rotein (MAP) kinases, ERK1 and ERK2, that persisted for at least 2 hr. This extracellular signal-regulated protein kinase (ERK) activation was inhibit ed successfully by the MEK1 inhibitor PD98059, but not by the estrogen rece ptor (ER) antagonist ICI 182,780: and did not appear to result from estradi ol-induced activation of trk. Furthermore, we also found that estradiol eli cited an increase in B-Raf kinase activity. The latter and subsequent downs tream events leading to ERK activation may be a consequence of our document ation of a multimeric complex consisting of, at least, the ER, hsp90, and B -Raf. These novel findings provide an alternative mechanism for some of the estrogen actions in the developing CNS and could explain not only some of the very rapid effects of estrogen but also the ability of estrogen and neu rotrophins to regulate the same broad array of cytoskeletal and growth-asso ciated genes involved in neurite growth and differentiation.