The EJC Factor eIF4AIII Modulates Synaptic Strength and Neuronal Protein Expression

Giorgi, Corinna; Yeo, G; Stone, Martha E.; Katz, Donald B.; Burge, Christopher B.; Turrigiano, Gina G.; Moore, Melissa J.

doi:10.1016/j.cell.2007.05.028

Cited by 288 publications

(354 citation statements)

References 68 publications

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“…Examination of Arc transcriptional foci by fluorescence in situ hybridization indicated prolonged (Ͼ1 h) transcriptional activation in dentate granule cells (56). Evidence from cultured hippocampal neurons further shows that Arc mRNA is rapidly degraded by non-sense mediated RNA decay by virtue of an exon junction complex in its 3Ј-untranslated region (57). In the extreme, Arc mRNA may be degraded after a single round of translation (58).…”

Section: Discussionmentioning

confidence: 99%

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Panja

Dagytė

Bidinosti

et al. 2009

Journal of Biological Chemistry

102

114

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Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2␣ on a protracted time course matching the time-window of Arc translation. Local infusion of the ERK inhibitor U0126 inhibited LTP maintenance and Arc protein expression, blocked changes in eIF4E and eIF2␣ phosphorylation state, and prevented initiation complex (eIF4F) formation. Surprisingly, inhibition of the mTOR protein complex 1 (mTORC1) with rapamycin did not impair LTP maintenance or Arc synthesis nor did it inhibit eIF4F formation or phosphorylation of eIF4E. Rapamycin nonetheless blocked mTOR signaling to p70 S6 kinase and ribosomal protein S6 and inhibited synthesis of components of the translational machinery. Using immunohistochemistry and in situ hybridization, we show that Arc protein expression depends on dual, ERK-dependent transcription and translation. Arc translation is selectively blocked by pharmacological inhibition of mitogen-activated protein kinase-interacting kinase (MNK), the kinase coupling ERK to eIF4E phosphorylation. Furthermore, MNK signaling was required for eIF4F formation. These results support a dominant role for ERK-MNK signaling in control of translational initiation and Arc synthesis during LTP consolidation in the dentate gyrus. In contrast, mTORC1 signaling is activated but nonessential for Arc synthesis and LTP. The work, thus, identifies translational control mechanisms uniquely tuned to Arc-dependent LTP consolidation in live rats.The adult mammalian brain is known to express diverse forms of activity-dependent synaptic plasticity (1, 2). Bursts of synaptic activity can induce short term changes in synaptic strength, but more stable modifications typically require modulation of gene expression at the transcriptional and post-transcriptional levels (3, 4). Through post-transcriptional regulation, synaptic activity may dictate the time and place of neuronal protein synthesis.Regulated phosphorylation of translation factors and other ribosome-associated proteins is a major mechanism for controlling the activity of the translational machinery (5, 6). Translation control studies of LTP 2 have concentrated mainly on the Schaffer-collateral input to hippocampal CA1 pyramidal cells. Studies employing knock-out mice and pharmacological inhibitors support a role for eukaryotic initiation factor 4E (eIF4E) and eIF2␣ in consolidation of LTP in the CA1 region and long term memory (7-10). The function of the cap-binding protein eIF4E during translational initiation is controlled by eIF4E-binding proteins (4E-BPs), which inhibit initiation complex (eIF4F) formation by competing with the scaffolding protein eIF4G for...

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Section: Discussionmentioning

confidence: 99%

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Panja

Dagytė

Bidinosti

et al. 2009

Journal of Biological Chemistry

102

114

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“…Previous analyses have identified 152 transcripts containing constitutive 3UIs that are conserved among human, rat, and mouse [51]. Interestingly, constitutive 3UI-containing transcripts that are conserved are particularly enriched in brain, testes, and hematopoietic cells [51]. We do not yet know the complete functional significance of these enrichments, but as described below, NMD is known to be involved in regulating developmental programs in both neurons and hematopoietic cells.…”

Section: Conservation and Tissuespecific Expression Of 3ui Genesmentioning

confidence: 98%

“…Such a splicing event can lead to mRNA down-regulation through a process known as alternative-splicing linked to NMD (AS-NMD) [50]. The third class consists of mRNAs that are constitutively spliced within the 3 0 -UTR [51]. These transcripts are expected to be degraded every time they are translated, unless the NMD pathway is inhibited.…”

Section: Splicing Directs Mrnp Formationmentioning

confidence: 99%

“…In the Illumina BodyMap deep sequencing data, we have identified 75 human genes for which the only detectable transcript(s) contain 3UIs more than 55 nts downstream of the translation termination codon, and these transcripts are expressed in a tissue-specific manner (Table 1). Previous analyses have identified 152 transcripts containing constitutive 3UIs that are conserved among human, rat, and mouse [51]. Interestingly, constitutive 3UI-containing transcripts that are conserved are particularly enriched in brain, testes, and hematopoietic cells [51].…”

Section: Conservation and Tissuespecific Expression Of 3ui Genesmentioning

confidence: 99%

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Introns in UTRs: Why we should stop ignoring them

et al. 2012

Self Cite

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Although introns in 5 0 -and 3 0 -untranslated regions (UTRs) are found in many protein coding genes, rarely are they considered distinctive entities with specific functions. Indeed, mammalian transcripts with 3 0 -UTR introns are often assumed nonfunctional because they are subject to elimination by nonsense-mediated decay (NMD). Nonetheless, recent findings indicate that 5 0 -and 3 0 -UTR intron status is of significant functional consequence for the regulation of mammalian genes. Therefore these features should be ignored no longer.

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“…Interestingly, YARS and eukaryotic eIF5 were found highly expressed into the varicosities (Jordanova et al, 2006;Luchessi et al, 2008). Another translation initiator factor, eIF4, resulted to modulate synaptic strength (Giorgi et al, 2007). Furthermore, the Jagged1 treatment induced the redistribution of the ribosomal protein L7a.…”

Section: Discussionmentioning

confidence: 99%

Notch activation induces neurite remodeling and functional modifications in SH‐SY5Y neuronal cells

Ferrari-Toninelli

Bonini

Uberti

et al. 2009

Developmental Neurobiology

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Notch proteins are definitely recognized as key regulators of the neuronal fate during embryo development, but their function in the adult brain is still largely unknown. We have previously demonstrated that Notch pathway stimulation increases microtubules stability followed by the remodeling of neuronal morphology with neurite varicosities loss, thicker neuritis, and enlarged growth cones. Here we show that the neurite remodeling is a dynamic event, dependent on transcription and translation, and with functional implications. Exposure of differentiated human SH-SY5Y neuroblastoma cells to the Notch ligand Jagged1 induces varicosities loss all along the neurites, accompanied by the redistribution of presynaptic vesicles and the decrease in neurotransmitters release. As evaluated by time lapse digital imaging, dynamic changes in neurite morphology were rapidly reversible and dependent on the activation of the Notch signaling pathway. In fact, it was prevented by the inhibition of the proteolytic c-secretase enzyme or the transcription machinery, and was mimicked by the transfection of the intracellular domain of Notch. One hour after treatment with Jagged1, several genes were downregulated. Many of these genes encode proteins that are known to be involved in protein synthesis. These data suggest that in adult neurons, Notch pathway activates a transcriptional program that regulates the equilibrium between varicosities formation and varicosities loss in the neuronal presynaptic compartment involving the expression and redistribution of both structural and functional proteins.

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The EJC Factor eIF4AIII Modulates Synaptic Strength and Neuronal Protein Expression

Cited by 288 publications

References 68 publications

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Introns in UTRs: Why we should stop ignoring them

Notch activation induces neurite remodeling and functional modifications in SH‐SY5Y neuronal cells

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