BC1 Regulation of Metabotropic Glutamate Receptor-Mediated Neuronal Excitability

Zhong, Jun; Chuang, Shih Chieh; Bianchi, R. M.; Zhao, Wangfa; Lee, Hee-Kyung; Fenton, André A.; Wong, Robert K. S.; Tiedge, Henri

doi:10.1523/jneurosci.3893-08.2009

Cited by 113 publications

(160 citation statements)

References 64 publications

(106 reference statements)

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“…Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47,48). These phenotypical manifestations are consonant with the molecular role of BC RNAs as translational repressors.…”

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confidence: 88%

“…Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1…”

mentioning

confidence: 99%

“…Ϫ/Ϫ animal model triggers increased group I metabotropic glutamate receptor-dependent synthesis of select synaptic proteins (47). Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47,48).…”

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confidence: 99%

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Dual Nature of Translational Control by Regulatory BC RNAs

Eom

Berardi

Zhong

et al. 2011

Molecular and Cellular Biology

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In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3 stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems.Translational control is an important means for the regulation of gene expression in eukaryotic cells (22). In neurons, the local translation of select mRNAs in synaptodendritic domains is considered a key determinant of neuronal function and plasticity (11,13,28,42). Strict control of local translation is essential to ensure that relevant proteins are synthesized only when and where needed (11). Progress has been made over the last 10 years as translational control mechanisms have been investigated in neurons, and several translational regulators have been identified (33,46). In one of these mechanisms, the effectors of neuronal translational control are regulatory BC RNAs (2,8,(43)(44)(45).Dendritic BC RNAs, neuronal small cytoplasmic RNAs (scRNAs) that include rodent BC1 RNA and primate BC200 RNA (20,21,40,41), are non-protein-coding RNAs that regulate translation at the level of initiation (43, 44). Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1Ϫ/Ϫ animal model triggers increased group I metabotropic glutamate receptor-dependent synthesis of select synaptic proteins (47). Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47, 48). These phenotypical manifestations are consonant with the molecular role of BC RNAs as translational repressors. BC1 RNA inhibits recruitment of the 43S preinitiation complex to the mRNA (44), a rate-limiting step in translation initiation that is mediated by the eIF4 family of eukaryotic initiation factors (6,9,12,31).The...

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mentioning

confidence: 88%

“…Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dual Nature of Translational Control by Regulatory BC RNAs

Eom

Berardi

Zhong

et al. 2011

Molecular and Cellular Biology

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“…Recently, BC1 RNA has been proposed to regulate, under synaptic activity, two FMRP target mRNAs: FMR1 and PSD-95 (Zhong et al, 2009), further linking FMRP and BC1 in the control of neuronal mRNA translation.…”

Section: Introductionmentioning

confidence: 99%

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

Maccarrone

Rossi

Bari

et al. 2010

Neuropsychopharmacol

111

103

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Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP acts as a translational repressor at central synapses, and molecular and synaptic plasticity studies have shown that the absence of this protein alters metabotropic glutamate 5 receptors (mGlu5Rs)-mediated signaling. In the striatum of mice lacking FMRP, we found enhanced activity of diacylglycerol lipase (DAGL), the enzyme limiting 2-arachidonoylglicerol (2-AG) synthesis, associated with altered sensitivity of GABA synapses to the mobilization of this endocannabinoid by mGlu5R stimulation with DHPG. Mice lacking another repressor of synaptic protein synthesis, BC1 RNA, also showed potentiated mGlu5R-driven 2-AG responses, indicating that both FMRP and BC1 RNA act as physiological constraints of mGlu5R/endocannabinoid coupling at central synapses. The effects of FMRP ablation on DAGL activity and on DHPG-mediated inhibition of GABA synapses were enhanced by simultaneous genetic inactivation of FMRP and BC1 RNA. In double FMRP and BC1 RNA lacking mice, striatal levels of 2-AG were also enhanced compared with control animals and to single mutants. Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXS, and identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

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“…Group I mGluR-induced epileptogenesis depends on activation of mRNA translation (Merlin et al, 1998) and is independent of transcription (Chuang et al, 2005). Recent studies indicate that the translation underlying epileptogenesis is regulated by a number of repressors including fragile X mental retardation protein (FMRP) (Chuang et al, 2005) and BC1 RNA (Zhong et al, 2009). These repressors safeguard normal subjects from group I mGluR-mediated epileptogenesis.…”

Section: Introductionmentioning

confidence: 99%