Single-molecule imaging of translational output from individual RNA granules in neurons

Tatavarty, Vedakumar; Ifrim, Marius F.; Levin, Mikhail K.; Korza, George; Barbarese, Elisa; Ji, Yu; Carson, John H.

doi:10.1091/mbc.e11-07-0622

Cited by 52 publications

(95 citation statements)

References 33 publications

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“…This does not seem to be the case with the SX-bodies, as they exclude the initiation factor eIF3g and rapidly dissolve upon polysome stabilization by cycloheximide, which does not affect stalled polysomes (Graber et al, 2013). For the same reasons, we speculate that active translation is not possible in the SX-bodies, even though translation occurs in a number of ribonucleoparticle (RNP) granules (Tatavarty et al, 2012;Yasuda et al, 2013;Pimentel and Boccaccio, 2014).…”

Section: What Is the Nature Of The Sx-bodies?mentioning

confidence: 91%

“…First, we monitored the local changes in the protein synthesis rate upon a short stimulation with 30 mM NMDA or 100 mM DHPG, which stimulates metabotropic receptors. We treated cultured hippocampal neurons with agonists as reported previously (Antar et al, 2004;Cougot et al, 2008;Park et al, 2008;Zeitelhofer et al, 2008;Baez et al, 2011;Tatavarty et al, 2012;Graber et al, 2013). We treated the neurons with tetrodotoxin (TTX), a drug that blocks voltagegated sodium channels and spontaneous activity, and then we exposed the cells to a 5-minute pulse of 30 mM NMDA or 100 mM DHPG (see Materials and Methods).…”

Section: Xrn1 Forms Synaptic Bodies That Are Different From Processinmentioning

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: What Is the Nature Of The Sx-bodies?mentioning

confidence: 91%

Section: Xrn1 Forms Synaptic Bodies That Are Different From Processinmentioning

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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“…Interestingly, Arc/Arg3.1, a critical regulator of AMPA receptor endocytosis, is translated within dendrites during mGlu-LTD (Waung et al, 2008). In another study, a single molecule imaging method showed that dendritic Arc/Arg3.1 translation is increased by mGlu receptor activation and decreased by action potential blockade (Tatavarty et al, 2012). These data suggest that regulating AMPA receptor expression might be one key function for local protein synthesis in dendrites.…”

Section: Dendritic Synthesis Of Specific Proteinsmentioning

confidence: 99%

“…While the results of these studies differed, it is clear that eEF1a is a dendritically regulated mRNA, and it will be interesting to determine whether altered levels of eEF1a affect local protein synthesis. The mRNA binding protein FMRP is also synthesized within dendrites, thus it is possible that its synthesis alters local mRNA translation and/or stability (Weiler et al, 1997, Tatavarty et al, 2012). Alternatively, locally synthesized RNA binding proteins could return to the nucleus or soma to bind new mRNA transcripts and transport them to dendrites.…”

Section: Dendritic Synthesis Of Specific Proteinsmentioning

confidence: 99%

Dendritic protein synthesis in the normal and diseased brain

Swanger

Bassell

2013

Neuroscience

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Synaptic activity is a spatially-limited process that requires a precise, yet dynamic, complement of proteins within the synaptic micro-domain. The maintenance and regulation of these synaptic proteins is regulated, in part, by local mRNA translation in dendrites. Protein synthesis within the postsynaptic compartment allows neurons tight spatial and temporal control of synaptic protein expression, which is critical for proper functioning of synapses and neural circuits. In this review, we discuss the identity of proteins synthesized within dendrites, the receptor-mediated mechanisms regulating their synthesis, and the possible roles for these locally synthesized proteins. We also explore how our current understanding of dendritic protein synthesis in the hippocampus can be applied to new brain regions and to understanding the pathological mechanisms underlying varied neurological diseases.

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“…HuR is typically most abundant in the nucleus of cells, but is known to translocate to the cytoplasm under certain conditions to facilitate mRNA stability and translation (36,37). If HuR is involved in the activitydependent translation of FMR1, it must be present at the synapse, because previous work has shown that endogenous FMR1 mRNA localizes to dendrites (38) and can be locally translated in an activity-dependent manner (39). To determine whether HuR is present at the synapse, we used immunocytochemistry to visualize its location in primary cortical neurons.…”

Section: Resultsmentioning

confidence: 99%

A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR

Suhl

Muddashetty

Anderson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Fragile X syndrome is a common cause of intellectual disability and autism spectrum disorder. The gene underlying the disorder, fragile X mental retardation 1 (FMR1), is silenced in most cases by a CGG-repeat expansion mutation in the 5′ untranslated region (UTR). Recently, we identified a variant located in the 3′UTR of FMR1 enriched among developmentally delayed males with normal repeat lengths. A patient-derived cell line revealed reduced levels of endogenous fragile X mental retardation protein (FMRP), and a reporter containing a patient 3′UTR caused a decrease in expression. A control reporter expressed in cultured mouse cortical neurons showed an expected increase following synaptic stimulation that was absent when expressing the patient reporter, suggesting an impaired response to neuronal activity. Mobility-shift assays using a control RNA detected an RNA–protein interaction that is lost with the patient RNA, and HuR was subsequently identified as an associated protein. Cross-linking immunoprecipitation experiments identified the locus as an in vivo target of HuR, supporting our in vitro findings. These data suggest that the disrupted interaction of HuR impairs activity-dependent translation of FMRP, which may hinder synaptic plasticity in a clinically significant fashion.

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Single-molecule imaging of translational output from individual RNA granules in neurons

Cited by 52 publications

References 33 publications

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Dendritic protein synthesis in the normal and diseased brain

A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR

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