title: Rapid signaling of estrogen to WAVE1 and moesin controls neuronal spine formation via the actin cytoskeleton.
abstract: 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 17beta-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 Galpha(i)/Gbeta protein-dependent, rapid extranuclear signaling of estrogen receptor alpha 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 Galpha(13)-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 alpha in neurons, which may be particularly relevant for the regulation of dendritic spines.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, 56100 Pisa, Italy.
authors.forename: Angel Matias
authors.initials: AM
authors.lastname: Sanchez
authors.forename: Marina Ines
authors.initials: MI
authors.lastname: Flamini
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Fu
authors.forename: Paolo
authors.initials: P
authors.lastname: Mannella
authors.forename: Maria Silvia
authors.initials: MS
authors.lastname: Giretti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Goglia
authors.forename: Andrea Riccardo
authors.initials: AR
authors.lastname: Genazzani
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000196:embryology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008840:Microfilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*
chemical_list: D000199:Actins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008840:Microfilament Proteins; D051300:Wiskott-Aldrich Syndrome Protein Family; C071058:moesin; D012694:Serine; D016392:Proto-Oncogene Proteins pp60(c-src); D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human