FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism

Darnell, Jennifer C.; Driesche, Sarah J. Van; Zhang, Chaolin; Hung, Ka Ying Sharon; Mele, Aldo; Fraser, Clive S.; Stone, Elizabeth F.; Chen, Cynthia; Fak, John; Wook, Sung; Licatalosi, Donny D.; Richter, Joel D.; Darnell, Robert B.

doi:10.1016/j.cell.2011.06.013

Cited by 1,925 publications

(2,698 citation statements)

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“…44 and E.P.R., unpublished data). Another abundant translational-regulatory protein that binds ribosomes and cross-links throughout CDS regions is the fragile X protein, FMRP 45 . FMRP, however, is a negative regulator of translation.…”

Section: Discussionmentioning

confidence: 99%

Staufen1 senses overall transcript secondary structure to regulate translation

Ricci

Küçükural

Cenik

et al. 2013

Nat Struct Mol Biol

122

184

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Human Staufen1 (Stau1) is a double-stranded RNA (dsRNA)-binding protein implicated in multiple post-transcriptional gene-regulatory processes. Here we combined RNA immunoprecipitation in tandem (RIPiT) with RNase footprinting, formaldehyde cross-linking, sonication-mediated RNA fragmentation and deep sequencing to map Staufen1-binding sites transcriptome wide. We find that Stau1 binds complex secondary structures containing multiple short helices, many of which are formed by inverted Alu elements in annotated 3′ untranslated regions (UTRs) or in 'strongly distal' 3′ UTRs. Stau1 also interacts with actively translating ribosomes and with mRNA coding sequences (CDSs) and 3′ UTRs in proportion to their GC content and propensity to form internal secondary structure. On mRNAs with high CDS GC content, higher Stau1 levels lead to greater ribosome densities, thus suggesting a general role for Stau1 in modulating translation elongation through structured CDS regions. Our results also indicate that Stau1 regulates translation of transcription-regulatory proteins.Staufen proteins are highly conserved dsRNA-binding proteins (dsRBPs) found in most bilateral animals 1 . Mammals contain two Staufen paralogs encoded by different loci. Stau1, Reprints and permissions information is available online at

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Section: Discussionmentioning

confidence: 99%

Staufen1 senses overall transcript secondary structure to regulate translation

Ricci

Küçükural

Cenik

et al. 2013

Nat Struct Mol Biol

122

184

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“…For instance, FMRP can recruit 4E-BP-like cytoplasmic Fmr-interacting protein 1 (CYFIP1) to repress the translation of target mRNAs (Napoli et al, 2008). Recent evidence indicate that FMRP can also repress the translation of cognate mRNAs through the association with miRNAs (Edbauer et al, 2010;Muddashetty et al, 2011) and through the reversible stalling of the ribosomes on polyribosomes containing FMRP-target mRNAs (Darnell et al, 2011).…”

Section: Trans-acting Factorsmentioning

confidence: 99%

BDNF-induced local protein synthesis and synaptic plasticity

2014

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a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

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“…As with the ribosomes, the top 1% of this RNA signal was detected in a subset of FXGs (Table 2). To identify specific mRNAs associated with these granules, we performed in situ hybridization for a panel of 21 candidates, including those that were both FMRP targets and reported to be present in axons of cultured neurons (Table 1, S1) (6,22,23). Most striking was association of FXGs with Ctnnb1 (b-catenin) mRNA (Fig.…”

Section: Ribosomes and Mrna In Brain Axonsmentioning

confidence: 99%

“…Tissue was homogenized in polysome lysis buffer as described (22). Lysate was precleared with protein A beads (Dynabeads, Life Technologies) for 1 h at 4 C. Immunoprecipitation was performed with the following antibodies pre-bound to protein A beads: rabbit anti-FMRP (Abcam 1772), rabbit anti-FXR2P (BU38) (14), mouse anti-rRNA (Y10b, specifically binds 5S and 5.8S rRNA), mouse or rabbit IgG.…”

Section: Rna Immunoprecipitationmentioning

confidence: 99%

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXGassociated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.

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FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism

Cited by 1,925 publications

References 98 publications

Staufen1 senses overall transcript secondary structure to regulate translation

Staufen1 senses overall transcript secondary structure to regulate translation

BDNF-induced local protein synthesis and synaptic plasticity

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

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