P-Body Components, microRNA Regulation, and Synaptic Plasticity

Hillebrand, Jens; Barbee, Scott A.; Ramaswami, Mani

doi:10.1100/tsw.2007.206

Cited by 29 publications

(25 citation statements)

References 84 publications

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“…* NS, nonspecific protein band. studies from several laboratories have strengthened the connection between miRNA-based regulation and PTGS in NGs (30). Here we report that Htt co-localizes with Ago2 in dendritic granules, and knockdown of Htt in dendrites results in altered Ago2 distribution.…”

Section: Discussionsupporting

confidence: 56%

“…To quantitatively assess Htt co-localization with these markers we examined multiple neurons and found that Htt dendritic granules often contained DCP1 (80.6%), Staufen (57.5%), and DDX6 (52.4%) ( Table 1). NGs are generally identified by the presence of Staufen, FMRP, and DDX6 (30). We thus provide evidence that Htt is present with two of the three NG markers.…”

Section: Resultssupporting

confidence: 50%

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A Role for Huntington Disease Protein in Dendritic RNA Granules

Savas

Deinhardt

et al. 2010

Journal of Biological Chemistry

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Regulated transport and local translation of mRNA in neurons are critical for modulating synaptic strength, maintaining proper neural circuitry, and establishing long term memory. Neuronal RNA granules are ribonucleoprotein particles that serve to transport mRNA along microtubules and control local protein synthesis in response to synaptic activity. Studies suggest that neuronal RNA granules share similar structures and functions with somatic P-bodies. We recently reported that the Huntington disease protein huntingtin (Htt) associates with Argonaute (Ago) and localizes to cytoplasmic P-bodies, which serve as sites of mRNA storage, degradation, and small RNAmediated gene silencing. Here we report that wild-type Htt associates with Ago2 and components of neuronal granules and cotraffics with mRNA in dendrites. Htt was found to co-localize with RNA containing the 3-untranslated region sequence of known dendritically targeted mRNAs. Knockdown of Htt in neurons caused altered localization of mRNA. When tethered to a reporter construct, Htt down-regulated reporter gene expression in a manner dependent on Ago2, suggesting that Htt may function to repress translation of mRNAs during transport in neuronal granules.

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Section: Discussionsupporting

confidence: 56%

Section: Resultssupporting

confidence: 50%

A Role for Huntington Disease Protein in Dendritic RNA Granules

Savas

Deinhardt

et al. 2010

Journal of Biological Chemistry

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“…dFmr1 and Atx2 orthologs in other species are present on Me31B-positive cytoplasmic mRNP aggregates related to stress granules (36,(60)(61)(62)(63). In addition, Atx2 function seems to be essential for the formation of Me31B-containing mRNP assemblies both in yeast as well as in mammalian cultured cells (39).…”

Section: Neuronal Atx2 and Dfmr1 Proteins Physically Associate And Bimentioning

confidence: 98%

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

Sudhakaran

Hillebrand

Dervan

et al. 2013

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

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114

147

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Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease-and stress granule-associated proteins implicated in neuronal translational control and microRNA function. We show that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells.synapse plasticity | olfactory memory | neural circuits | neurological disease

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“…By stage 6, the two proteins also colocalize in the oocyte cytoplasm ( Fig. 4M-P), which will eventually contain the polar granules, where Aub, dFmr1 and Vasa accumulate (Costa et al, 2005;Hillebrand et al, 2007;Thomson et al, 2008). dFmr1 does not seem to affect Aub expression, which still accumulates and localizes properly in dFmr1 ▵50 homozygous ovaries ( Fig.…”

Section: Dfmr1 and Aub Colocalize In Testis And Ovaries And Interact mentioning

confidence: 99%

The Drosophila fragile X mental retardation protein participates in the piRNA pathway

Bozzetti

Specchia

Cattenoz

et al. 2015

Journal of Cell Science

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RNA metabolism controls multiple biological processes, and a specific class of small RNAs, called piRNAs, act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation, and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNAbinding fragile X mental retardation protein (FMRP, also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here, we demonstrate for the first time that germline, as well as somatic expression, of Drosophila Fmr1 (denoted dFmr1), the Drosophila ortholog of FMRP, are necessary in a pathway mediated by piRNAs. Moreover, dFmr1 interacts genetically and biochemically with Aubergine, an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system.

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P-Body Components, microRNA Regulation, and Synaptic Plasticity

Cited by 29 publications

References 84 publications

A Role for Huntington Disease Protein in Dendritic RNA Granules

A Role for Huntington Disease Protein in Dendritic RNA Granules

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

The Drosophila fragile X mental retardation protein participates in the piRNA pathway

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