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dc.contributor.authorSteward, Oswalden
dc.contributor.authorYee, Kelly Matsudairaen
dc.contributor.authorFarris, Shannonen
dc.contributor.authorPirbhoy, Patricia S.en
dc.contributor.authorWorley, Paulen
dc.contributor.authorOkamura, Kohjien
dc.contributor.authorOkuno, Hiroyukien
dc.contributor.authorBito, Haruhikoen
dc.identifier.citationSteward O, Matsudaira Yee K, Farris S, Pirbhoy PS, Worley P, Okamura K, Okuno H and Bito H (2018) Delayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Mice. Front. Mol. Neurosci. 10:435. doi: 10.3389/fnmol.2017.00435en
dc.description.abstractArc is a unique immediate early gene (IEG) whose expression is induced as synapses are modified during learning. Newly-synthesized ArcmRNA is rapidly transported throughout dendrites and localizes near recently activated synapses. Arc mRNA levels are regulated by rapid degradation, which is accelerated by synaptic activity in a translation-dependent process. One possible mechanism is nonsense-mediated mRNA decay (NMD), which depends on the presence of a splice junction in the 3_UTR. Here, we test this hypothesis using transgenic mice that express EGFP-Arc. Because the transgene was constructed from Arc cDNA, it lacks intron structures in the 3_UTR that are present in the endogenous Arc gene. NMD depends on the presence of proteins of the exon junction complex (EJC) downstream of a stop codon, so EGFP-Arc mRNA should not undergo NMD. Assessment of Arc mRNA rundown in the presence of the transcription inhibitor actinomycin-D confirmed delayed degradation of EGFP-Arc mRNA. EGFP-Arc mRNA and protein are expressed at much higher levels in transgenic mice under basal and activated conditions but EGFP-Arc mRNA does not enter dendrites efficiently. In a physiological assay in which cycloheximide (CHX) was infused after induction of Arc by seizures, there were increases in endogenous Arc mRNA levels consistent with translation-dependent Arc mRNA decay but this was not seen with EGFP-Arc mRNA. Taken together, our results indicate: (1) Arc mRNA degradation occurs via a mechanism with characteristics of NMD; (2) rapid dendritic delivery of newly synthesized Arc mRNA after induction may depend in part on prior splicing of the 3_UTR.en
dc.description.sponsorshipGrant support: R01NS12333 to OS, R35NS097966 to PW, JSPS-KAKENHI grants 15H02358 and 17H06312 (to HB) and 15H04258 (to HO). PSP was the recipient of fellowship support from NIH MBRS-IMSD GM055246, NIH 5T32 NS045540, NIH NINDS F31 NS083349.en
dc.format.extent21 pagesen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.subjectsynaptic plasticityen
dc.subjectprotein synthesisen
dc.subjectdendritic mRNAen
dc.subjectdendritic spinesen
dc.subjectimmediate early geneen
dc.subjectnonsense-mediated decayen
dc.titleDelayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Miceen
dc.typeArticle - Refereeden
dc.title.serialFrontiers in Molecular Neuroscienceen

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Creative Commons Attribution 4.0 International
License: Creative Commons Attribution 4.0 International