Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice. Issue 167 (March 2017)

• Record Type: Journal Article
• Authors: Zhao, Yangang; Yu, Yanlan; Zhang, Yuanyuan; He, Li; Qiu, Linli; Zhao, Jikai; Liu, Mengying; Zhang, Jiqiang
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 167(2017)
• Page Start: 86
• Page End: 97
• Publication Date: 2017-03
• Subjects: Hippocampus -- Estrogens -- Aromatase -- Letrozole -- Steroid receptor coactivator-1 -- Actin cytoskeleton; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.11.013
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Hippocampal aromatase and actin polymerization are developmentally regulated. Letrozole inhibits hippocampal actin polymerization in vivo and in vitro . Estradiol rescue LET induced downregulation of actin remodeling proteins. SRC-1 knockdown suppresses E2 induced increased of actin remodeling proteins. Hippocampal E2 regulates actin polymerization in a SRC-1 dependent manner. Abstract: In the hippocampus, local estrogens (E2 ) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E2 synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E2, and E2 induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E2 inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E2 action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics.