Allele and genotype frequencies of <i>BDNF</i> polymorphism rs6265 (Val66Met) in control subjects and schizophrenic patients.

<p>Allele and genotype frequencies of <i>BDNF</i> polymorphism rs6265 (Val66Met) in control subjects and schizophrenic patients.</p

SNPs that modify miRNA binding sites according to PolymiRTS Database.

<p>PolymiRTS Database uses the criteria of TargetScan for miRNA binding sites prediction.</p>(a)<p>Support column indicates occurrence of the miRNA site in other vertebrate genomes in addition to the query genome.</p>(b)<p>Function Class specifies if the derived allele either disrupts a non conserved miRNA site (N) or creates a new miRNA site (C).</p

Luciferase assays for validation of miR-26a and -26b binding to <i>BDNF</i> 3′UTR.

<p>HeLa cells were independently transfected with control plasmid (pRL-TK) or each of the two reporter plasmid (pluc-BDNF C–G, anc, and pluc-BDNF A–T, der) with either miR-26a or miR-26b. Data are presented as the normalized activity of different reporter genes. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028656#s1" target="_blank">Introduction</a> of exogenous miR-26a and miR-26b represses reporter activity of pluc-BDNF C–G but has no effect on pluc-BDNF A–T. Data represent the mean of five independent experiments +SD (<i>p</i><0.05).</p

Analysis output with miRecords, that integrates predicted miRNA targets produced by 11 miRNA target prediction programs.

<p>Here are reported programs that predict <i>BDNF</i> 3′UTR miRna binding sites for miRNAs identified with PolymiRTS. Other programs are: DIANA-microT, MicroInspector, MirTarget2, miTarget, NBmiRTar, PicTar, TargetScan and RNA22.</p

Schematic representation of base pairing between miR-26a sequence and <i>BDNF</i> 3′UTR ancestral (C–G) and derivative (A–T) alleles of rs11030100 and rs11030099 polymorphic sites.

<p>MiR-26b has the same seed binding sequence.</p

Image_1_Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling.PDF

<p>Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3′ UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3′ UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3′ UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity.</p