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Rapid Signaling of Estrogen to WAVE1 and Moesin Controls Neuronal Spine Formation via the Actin Cytoskeleton

Molecular and Cellular Gynecological Endocrinology Laboratory (A.M.S., M.I.F., P.M., M.S.G., L.G., A.R.G., T.S.), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy; and Department of Physiology (X.-D.F.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

Address all correspondence and requests for reprints to: Tommaso Simoncini, M.D., Ph.D., Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma 57, 56100 Pisa, Italy. E-mail: t.simoncini{at}obgyn.med.unipi.it.

Estrogens are important regulators of neuronal cell morphology, and this is thought to be critical for gender-specific differences in brain function and dysfunction. Dendritic spine formation is dependent on actin remodeling by the WASP-family verprolin homologous (WAVE1) protein, which controls actin polymerization through the actin-related protein (Arp)-2/3 complex. Emerging evidence indicates that estrogens are effective regulators of the actin cytoskeleton in various cell types via rapid, extranuclear signaling mechanisms. We here show that 17β-estradiol (E2) administration to rat cortical neurons leads to phosphorylation of WAVE1 on the serine residues 310, 397, and 441 and to WAVE1 redistribution toward the cell membrane at sites of dendritic spine formation. WAVE1 phosphorylation is found to be triggered by a G_i/Gβ protein-dependent, rapid extranuclear signaling of estrogen receptor to c-Src and to the small GTPase Rac1. Rac1 recruits the cyclin-dependent kinase (Cdk5) that directly phosphorylates WAVE1 on the three serine residues. After WAVE1 phosphorylation by E2, the Arp-2/3 complex concentrates at sites of spine formation, where it triggers the local reorganization of actin fibers. In parallel, E2 recruits a G₁₃-dependent pathway to RhoA and ROCK-2, leading to activation of actin remodeling via the actin-binding protein, moesin. Silencing of WAVE1 or of moesin abrogates the increase in dendritic spines induced by E2 in cortical neurons. In conclusion, our findings indicate that the control of actin polymerization and branching via moesin or WAVE1 is a key function of estrogen receptor in neurons, which may be particularly relevant for the regulation of dendritic spines.

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Nuclear Receptors:   ERα

Ligands:   17β-Estradiol