Dendritic BC1 RNA in translational control mechanisms

Wang, Huidong; Iacoangeli, Anna; Lin, Daisy; Williams, Keith; Denman, Robert B.; Hellen, Christopher U.T.; Tiedge, Henri

doi:10.1083/jcb.200506006

Cited by 129 publications

(135 citation statements)

References 73 publications

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“…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). FMRP targets, on the other hand, include mRNAs with G-quartets (19,20), kissing complexes (29), and U-rich modules (30), among others.…”

Section: Resultsmentioning

confidence: 99%

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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: 99%

“…In view of the these data, it is concluded that in vitro BC1-FMRP interactions are nonspecific and are of low affinity. It is possible that many RNAs bind to FMRP in such nonspecific, low-affinity manner in vitro (5).…”

Section: Resultsmentioning

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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“…The limited number of functional studies of long ncRNAs reveal that they act via a diverse range of mechanisms in many regulatory processes, including transcription (Feng et al 2006), splicing (Yan et al 2005), translation (Wang et al 2005), nuclear factor trafficking (Willingham et al 2005), imprinting (Sleutels et al 2002;Thakur et al 2004), genome rearrangement (Nowacki et al 2007), and chromatin modification (Bernstein and Allis 2005;Rinn et al 2007). Comparative analysis of mouse long ncRNAs indicates that their promoters, primary sequence, and splice sites are under purifying selection (Ponjavic et al 2007).…”

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confidence: 99%

Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation

Dinger¹,

Amaral²,

Mercer³

et al. 2008

Genome Res.

700

584

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The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.

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“…B C1 and BC200 RNAs (1, 2), collectively called BC RNAs, are small untranslated RNAs that modulate gene expression at the level of translation (3)(4)(5)(6). BC RNAs are selectively expressed in neurons and are delivered to synaptodendritic compartments (1,2,(7)(8)(9), where they are thought to contribute to the regulation of local protein synthesis (3,4,6).…”

mentioning

confidence: 99%

“…BC RNAs are selectively expressed in neurons and are delivered to synaptodendritic compartments (1,2,(7)(8)(9), where they are thought to contribute to the regulation of local protein synthesis (3,4,6).…”

mentioning

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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270

191

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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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Dendritic BC1 RNA in translational control mechanisms

Cited by 129 publications

References 73 publications

On BC1 RNA and the fragile X mental retardation protein

On BC1 RNA and the fragile X mental retardation protein

Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation

Dendritic BC200 RNA in aging and in Alzheimer's disease

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