The RNA helicase DDX6 regulates cell-fate specification in neural stem cells via miRNAs

Nicklas, Sarah; Okawa, Satoshi; Hillje, Anna-Lena; Gonzalez-Cano, Laura; Sol, Antonio del; Schwamborn, Jens Christian

doi:10.1093/nar/gkv138

Cited by 50 publications

(58 citation statements)

References 65 publications

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“…DDX6 interacts with the CCR4-NOT complex and forms mutually exclusive interactions with multiple decapping factors 29,30,32,101 . In addition, DDX6 interacts with EDD and TRIM32, which have been implicated in miRNAmediated silencing 97,98 . This redundancy offers alternative ways to assemble silencing complexes, which might differ in their functional outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Current models are linked to RNA helicases: they involve either the initiation factor paralogues eIF4A1 and eIF4A2 (bona fide RNA helicases) or the translational repressor and decapping activator DDX6 (a putative RNA helicase). However, it is important to note that other proteins, including EDD 97 (also known as UBR5) and tripartite motif-containing protein 32 (TRIM32) 98 , have been implicated in the regulation of translational repression by mi RNAs through interactions with DDX6, but because even less is known about their mechanisms, we do not discuss them here. eIF4A-dependent mechanisms.…”

Section: Ccr4-not Links Translational Repression and Mrna Decaymentioning

confidence: 99%

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Towards a molecular understanding of microRNA-mediated gene silencing

2015

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MicroRNAs (miRNAs) are a conserved class of small non-coding RNAs that assemble with Argonaute proteins into miRNA-induced silencing complexes (miRISCs) to direct post-transcriptional silencing of complementary mRNA targets. Silencing is accomplished through a combination of translational repression and mRNA destabilization, with the latter contributing to most of the steady-state repression in animal cell cultures. Degradation of the mRNA target is initiated by deadenylation, which is followed by decapping and 5'-to-3' exonucleolytic decay. Recent work has enhanced our understanding of the mechanisms of silencing, making it possible to describe in molecular terms a continuum of direct interactions from miRNA target recognition to mRNA deadenylation, decapping and 5'-to-3' degradation. Furthermore, an intricate interplay between translational repression and mRNA degradation is emerging.

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Section: Discussionmentioning

confidence: 99%

Section: Ccr4-not Links Translational Repression and Mrna Decaymentioning

confidence: 99%

Towards a molecular understanding of microRNA-mediated gene silencing

2015

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“…The importance of let-7 for the differentiation of several cell lines, such as mouse neocortical cells (39) and neuronal stem cells (40), has been illustrated. Similarly, we have also observed the upregulation of let-7 miRNA with the differentiation of rat cortical neurons.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Ago2 and Subsequent Inactivation of let-7a RNP-Specific MicroRNAs Control Differentiation of Mammalian Sympathetic Neurons

Patranabis

Bhattacharyya

2016

Molecular and Cellular Biology

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MicroRNAs (miRNAs) are small regulatory RNAs that regulate gene expression posttranscriptionally by base pairing to the target mRNAs in animal cells. KRas, an oncogene known to be repressed by let-7a miRNAs, is expressed and needed for the differentiation of mammalian sympathetic neurons and PC12 cells. We documented a loss of let-7a activity during this differentiation process without any significant change in the cellular level of let-7a miRNA. However, the level of Ago2, an essential component that is associated with miRNAs to form RNP-specific miRNA (miRNP) complexes, shows an increase with neuronal differentiation. In this study, differentiation-induced phosphorylation and the subsequent loss of miRNA from Ago2 were noted, and these accounted for the loss of miRNA activity in differentiating neurons. Neuronal differentiation induces the phosphorylation of mitogen-activated protein kinase p38 and the downstream kinase mitogen-and stress-activated protein kinase 1 (MSK1). This in turn upregulates the phosphorylation of Ago2 and ensures the dissociation of miRNA from Ago2 in neuronal cells. MSK1-mediated miRNP inactivation is a prerequisite for the differentiation of neuronal cells, where let-7a miRNA gets unloaded from Ago2 to ensure the upregulation of KRas, a target of let-7a. We noted that the inactivation of let-7a is both necessary and sufficient for the differentiation of sympathetic neurons. P C12 cells derived from the pheochromocytoma of the rat adrenal medulla are widely used for studying cell signaling in response to numerous growth factors, neurotrophins, and hormones. These cells serve as a useful model to study the proliferation, differentiation, and survival of sympathetic neurons (1). PC12 cells stop dividing and differentiate to cells with neuronal extensions when cultured in the presence of nerve growth factor (NGF) and low levels of serum (2). Differentiated PC12 cells show changes in their electrical excitability, sensitivity to acetylcholine, and choline acetyltransferase activity (3). NGF-, brain-derived neurotrophic factor (BDNF)-, or cyclic AMP-treated, differentiated PC12 cells are connected to each other, although it is not clear whether newly formed neuronal extensions or neurites form functional synapses or not (4). The paradoxical finding that the Src and Ras oncogene products enhanced rather than blocked NGF-induced differentiation led to the identification of signaling pathways involving both Ras and Src as part of the total differentiation response to NGF (5). In PC12 cells, Ras accounts for the immediate effects of NGF, mediated through extracellular signal-regulated kinase (ERK) (1).MicroRNAs (miRNAs), a class of 21-nucleotide-long noncoding RNAs, can reversibly repress the translation of their target messages by binding the mRNA with imperfect complementarities in metazoan cells. miRNA-targeted messages and the components of the miRNA machinery, including the Argonaute (Ago) proteins and miRNAs, accumulate in mammalian P bodies (6-8). miRNAs can control neuronal differentiat...

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“…Moreover, non-RISC RBPs interact with miRNAs [29]. Tripartite motif containing 32 (TRIM32), together with the RNA helicase DDX6, increases the activity of the miRNA Let-7a during neuronal differentiation [30]. The best-studied interaction of RISCs occurs with Hu proteins [23].…”

Section: Mirna Silencing Complexes Behave Like 'Classical' Rna-bindinmentioning

confidence: 99%

Cooperativity in RNA–protein interactions: the complex is more than the sum of its partners

Achsel

Bagni

2016

Current Opinion in Neurobiology

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The RNA helicase DDX6 regulates cell-fate specification in neural stem cells via miRNAs

Cited by 50 publications

References 65 publications

Towards a molecular understanding of microRNA-mediated gene silencing

Towards a molecular understanding of microRNA-mediated gene silencing

Phosphorylation of Ago2 and Subsequent Inactivation of let-7a RNP-Specific MicroRNAs Control Differentiation of Mammalian Sympathetic Neurons

Cooperativity in RNA–protein interactions: the complex is more than the sum of its partners

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