miR-132 Regulates Dendritic Spine Structure by Direct Targeting of Matrix Metalloproteinase 9 mRNA

Abstract

Mir-132 is a neuronal activity-regulated microRNA that controls the morphology of dendritic spines and neuronal transmission. Similar activities have recently been attributed to matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease. In the present study, we provide evidence that miR-132 directly regulates MMP-9 mRNA in neurons to modulate synaptic plasticity. With the use of luciferase reporter system, we show that miR-132 binds to the 3’UTR of MMP-9 mRNA to regulate its expression in neurons. The overexpression of miR-132 in neurons reduces the level of endogenous MMP-9 protein secretion. In synaptoneurosomes, metabotropic glutamate receptor (mGluR)-induced signaling stimulates the dissociation of miR-132 from polyribosomal fractions and shifts it towards the messenger ribonucleoprotein (mRNP)-containing fraction. Furthermore, we demonstrate that the overexpression of miR-132 in the cultured hippocampal neurons from Fmr1 KO mice that have increased synaptic MMP-9 level provokes enlargement of the dendritic spine heads, a process previously implicated in enhanced synaptic plasticity. We propose that activity-dependent miR-132 regulates structural plasticity of dendritic spines through matrix metalloproteinase 9.

Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

“…The RNA co-immunoprecipitation with anti-FMRP antibody was performed as published before [40,43]. Briefly, 1.6 mg of total protein from freshly prepared synaptoneurosomes from hippocampi and a part of adjacent cerebral cortex of male P30-40 WT and Fmr1 KO mice were lysed in 1200 μl precipitation buffer (10 mM HEPES, pH 7.4, 200 mM NaCl, 30 mM EDTA, 0.5% Triton X-100) with protease inhibitor cocktail cOmplete (Roche, Indianapolis, IN) and 80 U/ml RiboLock RNase Inhibitor (Thermo Scientific).…”

Human thymic stromal lymphopoietin promotes the proliferation and invasion of cervical cancer cells by downregulating microRNA‑132 expression

“…An association has been found between MMP2 and MMP9 and the processes of tumor cell invasion and metastasis in multiple types of human cancer, including uterine neoplasms (39). Jasińska et al (40) reported that miR-132 regulated the structural plasticity of dendritic spines through directly repressing the expression of MMP9. In the present study, miR-132 significantly downregulated the expression of proliferation-associated proteins Ki-67 and PCNA, and invasion-associated enzymes MMP2 and MMP9 in CC cells, and further suppressed the proliferation and invasion of CC cells in vitro.…”

Metaloproteinaza macierzy pozakomórkowej 9 i epileptogeneza – kluczowa rola enzymu i strategie zmierzające do zapobiegania rozwojowi choroby

“…On the post-transcription level several pathways may activate the degradation of MMP-9 mRNAs [19]. Besides, regulations by microRNAs have been recently reported [20,21]. In neurons an additional level of MMP-9 regulation is its local translation in synapto-dendritic compartment.…”