Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1

Sosanya, Natasha M.; Huang, Peggy; Cacheaux, Luisa P.; Chen, Chun‐Jung; Nguyen, Kathleen T.; Perrone‐Bizzozero, Nora I.; Raab‐Graham, Kimberly F.

doi:10.1083/jcb.201212089

Cited by 104 publications

(134 citation statements)

References 70 publications

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“…mTOR is activated upon NMDAR stimulation and mediates the repression of a number of messengers and the translational activation of others (Sosanya et al, 2013). We found that the pharmacological inhibition of mTOR or of the upstream kinase phosphoinositide 3-kinase (PI3K) with specific drugs blocked the formation of synaptic XRN1 puncta triggered by NMDA (Fig.…”

Section: Xrn1 Forms Synaptic Bodies That Are Different From Processinmentioning

confidence: 92%

“…NMDAR stimulation affects translation through multiple mechanisms. It activates the mammalian/mechanistic target of rapamycin (mTOR), which in turn stimulates a number of translation factors and affects several miRNA targets in opposite directions (Weiler and Greenough, 1993;Banko et al, 2006;Sosanya et al, 2013). The integration of all these pathways results in the de-repression of a number of transcripts and the repression of others, and it was suggested that the reduction in the global protein synthesis rate induced by NMDA facilitates the translation of specific messengers, including that of Ca 2+ /CaM-dependent protein kinase II (CaMKII) and activity-regulated cytoskeletal-associated protein (Arc, also known as Arg3.1) mRNAs, which appear to compete poorly with other transcripts (Marin et al, 1997;Scheetz et al, 2000;Sutton et al, 2004;Sutton et al, 2006;Sutton et al, 2007;Park et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Luchelli¹,

Thomas²,

Boccaccio³

2015

Journal of Cell Science

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Repression of mRNA translation is linked to the formation of specific cytosolic foci such as stress granules and processing bodies, which store or degrade mRNAs. In neurons, synaptic activity regulates translation at the post-synapse and this is important for plasticity. Nmethyl-D-aspartate (NMDA) receptor stimulation downregulates translation, and we speculate that this is linked to the formation of unknown mRNA-silencing foci. Here, we show that the 59-39 exoribonuclease XRN1 forms discrete clusters associated with the post-synapse that are different from processing bodies or stress granules, and we named them synaptic XRN1 bodies (SX-bodies). Using primary neurons, we found that the SX-bodies respond to synapse stimulation and that their formation correlates inversely with the local translation rate. SX-bodies increase in size and number upon NMDA stimulation, and metabotropic glutamate receptor activation provokes SX-body dissolution, along with increased translation. The response is specific and the previously described Smaug1 foci and FMRP granules show a different response. Finally, XRN1 knockdown impairs the translational repression triggered by NMDA. Collectively, these observations support a role for the SX-bodies in the reversible masking and silencing of mRNAs at the synapse.

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Section: Xrn1 Forms Synaptic Bodies That Are Different From Processinmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Luchelli¹,

Thomas²,

Boccaccio³

2015

Journal of Cell Science

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“…Conversely, under conditions of inactive mTOR, association of the RBP HuD with AU-rich sequences on Kv1.1 mRNA was facilitated, resulting in an activation of Kv1.1 local translation. It was further suggested that the positive effect of HuD on Kv1.1 translation is the final result of the titration of other high affinity HuD targets [37] (figure 2a). In a different study, it was shown that the RISC-associated protein MOV10 is rapidly ubiquitinated and degraded upon membrane depolarization or activation of NMDA channels.…”

Section: Regulation Of Mirnas By Neuronal Activity (A) Activity-depenmentioning

confidence: 99%

MicroRNAs and synaptic plasticity—a mutual relationship

Aksoy‐Aksel

Zampa

Schratt

2014

Phil. Trans. R. Soc. B

107

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MicroRNAs (miRNAs) are rapidly emerging as central regulators of gene expression in the postnatal mammalian brain. Initial studies mostly focused on the function of specific miRNAs during the development of neuronal connectivity in culture, using classical gain-and loss-of-function approaches. More recently, first examples have documented important roles of miRNAs in plastic processes in intact neural circuits in the rodent brain related to higher cognitive abilities and neuropsychiatric disease. At the same time, evidence is accumulating that miRNA function itself is subjected to sophisticated control mechanisms engaged by the activity of neural circuits. In this review, we attempt to pay tribute to this mutual relationship between miRNAs and synaptic plasticity. In particular, in the first part, we summarize how neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals. In the second part, we discuss recent examples of miRNA function in synaptic plasticity in rodent models and their implications for higher cognitive function and neurological disorders, with a special emphasis on epilepsy as a disorder of abnormal nerve cell activity.

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“…Many of the alcohol-responsive adaptations are related to synaptic structure and function and may be caused by coordinated changes in local mRNA translation Mayfield and Nunez, 2012). MicroRNAs are short, noncoding RNAs that can regulate the translation of many target mRNAs, and this process is known to occur in the synaptic compartments of the cell (Lugli et al, 2005(Lugli et al, ,2008Smalheiser and Lugli, 2009;Sosanya et al, 2013). The ability of microRNAs to regulate mRNAs provides a localized regulatory system that may be important in the treatment of alcoholism.…”

Section: Introductionmentioning

confidence: 99%

“…Synaptoneurosomes (SN) (Hollingsworth et al, 1985;Quinlan et al, 1999;Raab-Graham et al, 2006;Sosanya et al, 2013) contain membrane vesicles of pre-and postsynaptic compartments of neurons as well as peri-synaptic compartments of astrocytes and microglia and offer an improved model for studying the synaptic transcriptome. We recently showed that alcohol-induced mRNA changes are greater in SN compared with TH (Most et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption

Most

Leiter

Blednov

et al. 2015

Neuropsychopharmacol

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Local translation of mRNAs in the synapse has a major role in synaptic structure and function. Chronic alcohol use causes persistent changes in synaptic mRNA expression, possibly mediated by microRNAs localized in the synapse. We profiled the transcriptome of synaptoneurosomes (SN) obtained from the amygdala of mice that consumed 20% ethanol (alcohol) in a 30-day continuous two-bottle choice test to identify the microRNAs that target alcohol-induced mRNAs. SN are membrane vesicles containing pre-and post-synaptic compartments of neurons and astroglia and are a unique model for studying the synaptic transcriptome. We previously showed that chronic alcohol regulates mRNA expression in a coordinated manner. Here, we examine microRNAs and mRNAs from the same samples to define alcohol-responsive synaptic microRNAs and their predicted interactions with targeted mRNAs. The aim of the study was to identify the microRNA-mRNA synaptic interactions that are altered by alcohol. This was accomplished by comparing the effect of alcohol in SN and total homogenate preparations from the same samples. We used a combination of unbiased bioinformatic methods (differential expression, correlation, co-expression, microRNA-mRNA target prediction, co-targeting, and cell type-specific analyses) to identify key alcohol-sensitive microRNAs. Prediction analysis showed that a subset of alcohol-responsive microRNAs was predicted to target many alcohol-responsive mRNAs, providing a bidirectional analysis for identifying microRNA-mRNA interactions. We found microRNAs and mRNAs with overlapping patterns of expression that correlated with alcohol consumption. Cell type-specific analysis revealed that a significant number of alcohol-responsive mRNAs and microRNAs were unique to glutamate neurons and were predicted to target each other. Chronic alcohol consumption appears to perturb the coordinated microRNA regulation of mRNAs in SN, a mechanism that may explain the aberrations in synaptic plasticity affecting the alcoholic brain.

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Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1

Abstract: Inhibition of mTORC1 leads to the degradation of high affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA and promote its translation by overcoming miR-129–mediated repression.

Cited by 104 publications

References 70 publications

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

MicroRNAs and synaptic plasticity—a mutual relationship

Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption

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