Rna Transport and Local Control of Translation

Kindler, Stefan; Wang, Huidong; Richter, Dietmar; Tiedge, Henri

doi:10.1146/annurev.cellbio.21.122303.120653

Cited by 178 publications

(187 citation statements)

References 158 publications

(66 reference statements)

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“…The results (Fig. 5B) (2,3,9,28). BC1 RNA inhibits recruitment of 43S preinitiation complexes to mRNAs; it therefore targets translation particularly of mRNAs with structured 5Ј UTRs that require eIF4A-mediated unwinding (4,5).…”

Section: Resultsmentioning

confidence: 90%

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On BC1 RNA and the fragile X mental retardation protein

Iacoangeli¹,

Rozhdestvensky

Dolzhanskaya

et al. 2008

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

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The fragile X mental retardation protein (FMRP), the functional absence of which causes fragile X syndrome, is an RNA-binding protein that has been implicated in the regulation of local protein synthesis at the synapse. The mechanism of FMRP's interaction with its target mRNAs, however, has remained controversial. In one model, it has been proposed that BC1 RNA, a small nonprotein-coding RNA that localizes to synaptodendritic domains, operates as a requisite adaptor by specifically binding to both FMRP and, via direct base-pairing, to FMRP target mRNAs. Other models posit that FMRP interacts with its target mRNAs directly, i.e., in a BC1-independent manner. Here five laboratories independently set out to test the BC1-FMRP model. We report that specific BC1-FMRP interactions could be documented neither in vitro nor in vivo. Interactions between BC1 RNA and FMRP target mRNAs were determined to be of a nonspecific nature. Significantly, the association of FMRP with bona fide target mRNAs was independent of the presence of BC1 RNA in vivo. The combined experimental evidence is discordant with a proposed scenario in which BC1 RNA acts as a bridge between FMRP and its target mRNAs and rather supports a model in which BC1 RNA and FMRP are translational repressors that operate independently.fragile X syndrome ͉ non-protein-coding RNAs ͉ translational control S mall non-protein-coding RNAs perform important functions in the regulation of eukaryotic gene expression (1). In the mammalian central nervous system, they have been implicated in promoting organism-environment interactions (2). Small untranslated BC1 RNA is a translational repressor that is thought to participate in the regulation of local protein synthesis at the synapse (2, 3). BC1 RNA represses translation by targeting assembly of 48S initiation complexes (4). Interacting with eukaryotic initiation factor 4A (eIF4A) and poly(A) binding protein (PABP) (4-6), BC1 RNA prevents recruitment of the 43S preinitiation complex to the mRNA. Targets of BC1-mediated repression are those mRNAs that depend on the eIF4 family of factors for efficient initiation (4).Fragile X syndrome is caused by the functional absence of fragile X mental retardation protein (FMRP) (7,8). Consensus has developed over recent years that FMRP is, like BC1 RNA, a translational repressor that is active in postsynaptic microdomains (7, 9, 10). However, in contrast to BC1 RNA, FMRP is associated with polysomes (11-15), indicating that BC1 RNA and FMRP operate at different levels in the translation pathway.In an alternative model, it has been proposed that BC1 RNA and FMRP interact directly with each other (16,17). In this scenario, BC1 RNA (i) physically binds to FMRP, (ii) directly interacts, by base-pairing of its 5Ј domain, with select mRNAs that are FMRP targets, and (iii) acts as a bridge between FMRP and such target mRNAs, thus serving as a requisite adaptor (16, 17).The above two models cannot be reconciled. We, five independent groups with a longstanding interest in the molecular biology of...

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Section: Resultsmentioning

confidence: 90%

“…In the mammalian central nervous system, they have been implicated in promoting organism-environment interactions (2). Small untranslated BC1 RNA is a translational repressor that is thought to participate in the regulation of local protein synthesis at the synapse (2,3). BC1 RNA represses translation by targeting assembly of 48S initiation complexes (4).…”

mentioning

confidence: 99%

On BC1 RNA and the fragile X mental retardation protein

Iacoangeli¹,

Rozhdestvensky

Dolzhanskaya

et al. 2008

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

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“…Increasing evidence suggests that dendritic protein synthesis is instrumental in the implementation of long-term plastic changes at the synapse (10)(11)(12)(13)(14) and that small untranslated RNAs are intimately involved in such local translational control (6,15). On-site translation of locally available mRNAs could provide a means for the input-specific modulation of synaptic strength, thus allowing for adaptive responses to external stimuli.…”

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confidence: 99%

Dendritic BC200 RNA in aging and in Alzheimer's disease

Mus¹,

Hof

Tiedge

2007

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

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275

199

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Small untranslated BC1 and BC200 RNAs are translational regulators that are selectively targeted to somatodendritic domains of neurons. They are thought to operate as modulators of local protein synthesis in postsynaptic dendritic microdomains, in a capacity in which they would contribute to the maintenance of long-term synaptic plasticity. Because plasticity failure has been proposed to be a starting point for the neurodegenerative changes that are seen in Alzheimer's disease (AD), we asked whether somatodendritic levels of human BC200 RNA are deregulated in AD brains. We found that in normal aging, BC200 levels in cortical areas were reduced by >60% between the ages of 49 and 86. In contrast, BC200 RNA was significantly up-regulated in AD brains, in comparison with age-matched normal brains. This up-regulation in AD was specific to brain areas that are involved in the disease. Relative BC200 levels in those areas increased in parallel with the progression of AD, as reflected by Clinical Dementia Rating scores. In more advanced stages of the disease, BC200 RNA often assumed a clustered perikaryal localization, indicating that dendritic loss is accompanied by somatic overexpression. Mislocalization and overexpression of BC200 RNA may be reactive-compensatory to, or causative of, synaptodendritic deterioration in AD neurons.dementia ͉ non-protein-coding RNA ͉ RNA transport

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“…Further experiments are needed. As for the mRNA transport, motor proteins, including both kinesin and dynein motors, have been demonstrated to participate in RNP complex transport in many eukaryotic cell types [14,43]. In Drosophila, DmKHC is required for posterior localization of oskar mRNA [44].…”

Section: Filamentous Tubulin Colocalizationmentioning

confidence: 99%