Noncoding Rnas in the Mammalian Central Nervous System

Cao, Xinwei; Yeo, G; Muotri, Alysson R.; Kuwabara, Tomoko; Gage, Fred H.

doi:10.1146/annurev.neuro.29.051605.112839

Cited by 400 publications

(333 citation statements)

References 146 publications

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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).…”

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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“…Currently, microRNAs are undergoing evaluation for possible clinical use as biomarkers for neurological diseases (de Planell-Saguer and Rodicio, 2011). The brain expresses 70% of known microRNAs, each of which exhibits distinctive spatio-temporal expression (Cao et al, 2006; de Planell-Saguer and Rodicio, 2011). Dysregulation of microRNA expression have been found in animal models of Alzheimer's disease (Hebert et al, 2009).…”

Section: Future Research Directionsmentioning

confidence: 99%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.

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“…ment and function has been steadily growing. Recent years have seen a tremendous increase in the number of miRNAs recognized as being either specifically expressed or at least enriched in the mammalian nervous system [24,25].…”

Section: Mirna and Brain Functionmentioning

confidence: 99%

MicroRNAs in brain function and disease

Kuß

Chen²

2008

Curr Neurol Neurosci Rep

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MicroRNAs (miRNAs), a class of small, non-protein-coding transcripts about 21 nucleotides long, have recently entered center stage in the study of posttranscriptional gene regulation. They are now thought to be involved in the control of about one third of all protein-coding genes and play a role in the majority of cellular processes that have been studied. We focus on the role of the miRNA pathway in brain development, function, and disease by highlighting recent observations with respect to miRNAmediated gene regulation in neuronal differentiation, synaptic plasticity, and the circadian clock. We also discuss the implications of these findings with respect to the involvement of miRNAs in the etiopathology of brain disorders and pinpoint the emerging therapeutic potential of miRNAs for the treatment of human diseases.

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Noncoding Rnas in the Mammalian Central Nervous System

Cited by 400 publications

References 146 publications

On BC1 RNA and the fragile X mental retardation protein

On BC1 RNA and the fragile X mental retardation protein

Epigenetic Mechanisms in Stroke and Epilepsy

MicroRNAs in brain function and disease

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