| Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA-processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28- regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNFresponsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part post-transcriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182, while selectively de-repressing and increasing translation of specific mRNAs.;This work demonstrates for the first time how specificity in neurotrophin-dependent protein synthesis is achieved, and raises interesting questions regarding the underlying mechanisms of this pathway. To further expand our understanding of mechanisms regulating specificity in neuronal translation, we have also undertaken a comprehensive characterization of BDNF-induced mRNA repression at synapses. These experiments may have far-reaching implications for understanding rapid changes in synaptic protein content and, ultimately, may generate opportunities for translation to therapeutic intervention. |
