Transcript specificity in BDNF-regulated protein synthesis

Abstract

Brain-derived neurotrophic factor (BDNF) is a critical activity-dependent modulator of gene expression, which can regulate both transcription and translation. Several functions of BDNF, including the induction of dendrite outgrowth and long-term synaptic plasticity, are known to depend, in particular, upon the ability of BDNF to regulate protein synthesis. Although BDNF modestly increases total neuronal protein synthesis, substantial evidence indicates that BDNF induces the translation of only a small subset of expressed mRNAs and demonstrates an extraordinary degree of transcript specificity. The mechanism by which BDNF selectively upregulates the translation of only a discrete group of mRNAs is of intrinsic importance to its trophic function in promoting neuronal growth and plasticity, and is the focus of this review. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

Keywords: BDNF; Let-7; Lin28; Post-transcriptional regulators; Protein synthesis; RNA-binding proteins; Synaptic plasticity; microRNAs.

Figure 1. BDNF exerts post-transcriptional control of protein synthesis through regulation of miRNA-dependent repression

miRNA-mediated repression can be regulated by BDNF to provide general (left panel) or miRNA-selective (right panel) control of translation. miRNA-selective effects of BDNF on the efficacy of repression (miR-134) (Schratt et al., 2006)or abundance (Let-7 family miRNAs; (Huang et al., 2012)) for particular miRNAs, can reduce repression by particular miRNAs and impart transcript specificity to the induction of protein synthesis by BDNF. BDNF stimulation upregulates Lin28, an RNA binding protein that can bind precursors of the Let-7 miRNA family (Let-7 pre-miRNA), preventing them from being processed by the Dicer-TRBP machinery. The resulting diminished levels of mature Let-7 miRNAs relieve repression of mRNAs with Let-7 binding sites and permit their translation. BDNF can also regulate miRNA-mediated repression in a global manner that is not selective for a particular miRNA family (left panel). By facilitating the phosphorylation of TRBP, BDNF stabilizes and enhances levels of the Dicer-TRBP complex that processes pre-miRNA into mature miRNA. This leads to a general rapid increase in miRNA levels and, in turn, increased miRNA-mediated repression of many transcripts. BDNF also modulates NMDA-receptor dependent signaling which has been shown to produce general effects on RISC-dependent mRNA repression. NMDA-dependent signaling induces proteasome-dependent degradation of MOV10, a component of RISC, leading to a loss of RISC function and freeing repressed mRNA to enable translation (as was demonstrated for the CaMKIIα transcript).