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.

17-β-Estradiol increases neuronal excitability through MAP kinase-induced calpain activation

“…kinase, thereby leading to actin polymerization and increased formation of filopodia (18,19). As calpain inhibition prevented E2-induced increase in actin polymerization, our results indicate that calpain activation is an important step leading to actin polymerization, possibly through cofilin phosphorylation/inactivation.…”

“…Several studies have shown that E2 participates in the regulation of dendritic spine morphology in area CA1 of hippocampus (18,19). E2 has been shown to inactivate cofilin by stimulating LIM 5.…”

“…It has been shown that E2 facilitates LTP by activation of the Src/MAP kinase pathway and subsequent phosphorylation of NMDA receptors (13)(14)(15). Recent data indicate that the rapid effects of E2 on synaptic function and plasticity are mediated by alterations of the cytoskeletal network, especially by stimulation of actin polymerization (16)(17)(18)(19). Furthermore, although the respective roles of the two types of E2 receptors, ER␣ and ER␤, are still debated, several lines of evidence indicate that the rapid effects of E2 on synaptic function are mediated by ER␤ rather than ER␣ receptors (20).…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…In young, cultured cortical neurons, treatment with 10 nM 17b-estradiol resulted in a rapid increase in the number of filopodia. This effect was maximal after 20 minutes of treatment but was transient because the number of filopodia returned to pretreatment levels by 60 minutes (Sanchez et al, 2009). The ability of 17b-estradiol to rapidly remodel dendritic filopodia in young, developing neurons indicates a role for estrogens in Rapid Modulation of Neuroplasticity by Brain Estrogens modulating synaptogenesis during early development of cortical circuitry.…”

“…In young developing cortical neurons, 17b-estradiol-mediated filopodia formation occurs via the activation of a c-SRC/Rac1/Cdk5/ WAVE1/Arp2/3 pathway and a RhoA/ROCK-2/moesin cascade (Sanchez et al, 2009). Although phosphorylation of WAVE1 was only achieved by 17b-estradiol and PPT, but not DPN, suggesting an ERa-dependent pathway, the direct effects of ERa activation on filopodial formation was not tested.…”