Abstract
Argonaute (AGO) proteins are essential components of the microRNA (miRNA) pathway. AGO proteins are loaded with miRNAs to target mRNAs and thereby regulate mRNA stability and protein translation. As such, AGO proteins are important actors in controlling local protein synthesis, for instance, at dendritic spines and synapses. Although miRNA-mediated regulation of dendritic mRNAs has become a focus of intense interest over the past years, the mechanisms regulating neuronal AGO proteins remain largely unknown. Here, using rat hippocampal neurons, we report that dendritic Ago2 is down-regulated by the proteasome upon NMDA receptor activation. We found that Ser-387 in Ago2 is dephosphorylated upon NMDA treatment and that this dephosphorylation precedes Ago2 degradation. Expressing Ser-387 phosphorylation-deficient or phosphomimetic Ago2 in neurons, we observed that this phosphorylation site is involved in modulating dendritic spine morphology and postsynaptic density protein 95 (PSD-95) expression in spines. Collectively, our results point toward a signaling pathway linking NMDA receptor-dependent Ago2 dephosphorylation and turnover to postsynaptic structural changes. They support a model in which NMDA receptor-mediated dephosphorylation of Ago2 and Ago2 turnover contributes to the de-repression of mRNAs involved in spine growth and maturation.
Highlights
IntroductionAGO proteins are loaded with miRNAs to target messenger RNAs (mRNAs) and thereby regulate mRNA stability and protein translation
Argonaute (AGO) proteins are essential components of the microRNA pathway
Incubation with PTX induced a significant loss of Ago2 in dendrites (Fig. S2), which was blocked by co-incubation with the NMDA-R antagonist APV (AP5) thereby indicating again that NMDA-R stimulation is causing the loss of Ago2
Summary
AGO proteins are loaded with miRNAs to target mRNAs and thereby regulate mRNA stability and protein translation. Expressing Ser-387 phosphorylation– deficient or phosphomimetic Ago in neurons, we observed that this phosphorylation site is involved in modulating dendritic spine morphology and postsynaptic density protein 95 (PSD-95) expression in spines. Our results point toward a signaling pathway linking NMDA receptor– dependent Ago dephosphorylation and turnover to postsynaptic structural changes. They support a model in which NMDA receptor–mediated dephosphorylation of Ago and Ago turnover contributes to the de-repression of mRNAs involved in spine growth and maturation. Several studies have shown that the association of miRISC with different scaffold or RNA-binding proteins underlies the translational regulation associated with synaptogenesis and synaptic plasticity [22,23,24,25,26,27]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
