Rapid Estrogen and Progesterone Signaling to Dendritic Spine Formation via Cortactin/Wave1-Arp2/3 Complex

Abstract

Background: Synaptic plasticity is the neuronal capacity to modify the function and structure of dendritic spines (DS) in response to neuromodulators. Sex steroids, particularly 17β-estradiol (E2) and progesterone (P4), are key regulators in the control of DS formation through multiprotein complexes including WAVE1 protein, and are thus fundamental for the development of learning and memory. Objectives: The aim of this work was to evaluate the molecular switch Cdk5 kinase/protein phosphatase 2A (PP2A) in the control of WAVE1 protein (phosphorylation/dephosphorylation) and the regulation of WAVE1 and cortactin to the Arp2/3 complex, in response to rapid treatments with E2 and P4 in cortical neuronal cells. Results: Rapid treatment with E2 and P4 modified neuronal morphology and significantly increased the number of DS. This effect was reduced by the use of a Cdk5 inhibitor (Roscovitine). In contrast, inhibition of PP2A with PP2A dominant negative construct significantly increased DS formation, evidencing the participation of kinase/phosphatase in the regulation of WAVE1 in DS formation induced by E2 and P4. Cortactin regulates DS formation via Src and PAK1 kinase induced by E2 and P4. Both cortactin and WAVE1 signal to Arp2/3 complex to synergistically promote actin nucleation. Conclusion: These results suggest that E2 and P4 dynamically regulate neuron morphology through nongenomic signaling via cortactin/WAVE1-Arp2/3 complex. The control of these proteins is tightly orchestrated by phosphorylation, where kinases and phosphatases are essential for actin nucleation and, finally, DS formation. This work provides a deeper understanding of the biological actions of sex steroids in the regulation of DS turnover and neuronal plasticity processes.

Molecular Basis of LH Action on Breast Cancer Cell Migration and Invasion via Kinase and Scaffold Proteins

“…Here, we demonstrate that LH disrupts the basal FAK/cortactin/Arp3 subunit interaction and that this effect can be prevented with the specific Src inhibitor (PP2). Similarly, we recently reported that sex steroid treatment diminishes the association between cortactin and the Arp3 subunit in cortical neuron cells (Uzair et al, 2020). We propose that the specific phosphorylation of these proteins affects their interaction as a consequence of physical impediments involving a cycle of binding, phosphorylation, and subsequent dissociation accompanied by FA turnover and cell movement.…”

Restoring Wnt signaling in a hormone-simulated postpartum depression model remediated imbalanced neurotransmission and depressive-like behaviors

“…Variations in reproductive hormone levels represent an obvious risk factor for postpartum depression (Payne and Maguire 2019 ). Oestrogen and progesterone have been established to influence neuroplasticity in many brain regions, particularly mediating neurogenesis in hippocampal formation (Sheppard et al 2019 ; Uzair et al 2020 ). We confirmed the familiar consequences identified in previous research (Suda et al 2008 ) that animals displayed hopelessness and anhedonia in the escape failure test after inescapable stress and the sucrose preference test after hormone withdrawal (Fig.…”