HuD Promotes BDNF Expression in Brain Neurons via Selective Stabilization of the BDNF Long 3′UTR mRNA

Megan Allen,Clark Bird,Nora I. Perrone-Bizzozero,Yue Feng,Wenqi Li,Wei Feng,Guanglu Liu,Michal Hetman

doi:10.1371/journal.pone.0055718

Megan Allen, Clark Bird + Show 6 more

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https://doi.org/10.1371/journal.pone.0055718

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Journal: PloS one	Publication Date: Jan 31, 2013
Citations: 55	License type: CC BY 4.0

Affiliation: University of New Mexico, Emory University

Abstract

Complex regulation of brain-derived neurotrophic factor (BDNF) governs its intricate functions in brain development and neuronal plasticity. Besides tight transcriptional control from multiple distinct promoters, alternative 3′end processing of the BDNF transcripts generates either a long or a short 3′untranslated region (3′UTR). Previous reports indicate that distinct RNA sequence in the BDNF 3′UTRs differentially regulates BDNF production in the brain to accommodate neuronal activity changes, conceivably through differential interactions with undefined trans-acting factors that regulate stability and translation of these BDNF mRNA isoforms. In this study, we report that the neuronal RNA-binding protein (RBP) HuD interacts with a highly conserved AU-rich element (ARE) specifically located in the BDNF long 3′UTR. Such interaction is necessary and sufficient for selective stabilization of mRNAs that contain the BDNF long 3′UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model, the BDNF long 3′UTR mRNA is increased in the hippocampal dentate granule cells (DGCs), leading to elevated expression of BDNF protein that is transported and stored in the mossy fiber (MF) terminals. Our results identify HuD as the first trans-acting factor that enhances BDNF expression specifically through the long 3′UTR and a novel mechanism that regulates BDNF protein production in selected neuronal populations by HuD abundance.

Highlights

Brain-derived neurotrophic factor (BDNF) plays pivotal roles in governing a broad spectrum of brain functions including neuronal survival, neural network development, and synaptic plasticity
Using the ARED-Organisms database, we identified a highly conserved Class I AU-rich element (ARE) located in the BDNF long 39untranslated region (39UTR) immediately up-stream of the distal polyadenylation site (Figure 1A), suggesting that ARE-binding proteins (ARE-BPs) may preferentially regulate stability of the BDNF long 39UTR mRNA
Our studies identify HuD as the first RNA-binding protein (RBP) that selectively binds to and stabilizes the BDNF long 39UTR mRNA but not the short BDNF mRNA

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) plays pivotal roles in governing a broad spectrum of brain functions including neuronal survival, neural network development, and synaptic plasticity. To accommodate such intricate functions, BDNF expression is under precise regulation. Besides the sophisticated transcriptional regulation, alternative polyadenylation of the BDNF transcripts results in two pools of BDNF mRNAs that carry either a short or a long 39untranslated region (UTR), regardless of which promoter drives BDNF transcription [3,7]. The long 39UTR, but not the short 39UTR, suppresses BDNF translation in the resting brain and mediates neuronal activity-dependent translation of BDNF [8]. The long 39UTR can target BDNF mRNA into dendrites thereby governing dendritic BDNF protein abundance [8,9]

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