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

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.

Alternative polyadenylation diversifies post‐transcriptional regulation by selective RNA–protein interactions

“…Although differences in the 5′ UTR may also contribute to RNA decay (Trcek et al , ), our results demonstrate genome‐wide that multiple mRNA messages encoding the same protein‐coding sequence that differ only in their 3′ UTR can have divergent post‐transcriptional lifetimes. This finding is in agreement with previous reports describing the potential role of the 3′ UTR in regulating stability and represents the first such genome‐wide confirmation in yeast (Goodarzi et al , ; Allen et al , ; Ray et al , ).…”

“…Some studies have shown that the production of shorter 3′ isoforms leads to higher translation efficiency due to the exclusion of miRNA‐binding sites present in the longer isoforms (Sandberg et al , ; Mayr & Bartel, ). Another study has demonstrated that the RNA‐binding protein (RBP) HuD regulates the stability of the gene coding for the brain‐derived neurotrophic factor in an isoform‐specific manner (Allen et al , ). RBPs can act as regulators of gene expression, controlling post‐transcriptional processes and often binding to 3′ UTRs (Ray et al , ).…”

Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis

“…Given that HuD KO mice exhibit altered embryonic brain development (4), to determine the role of HuD in adult neurogenesis without the confound of developmental impact, we acutely deleted HuD in NSCs in the adult SVZ using retrovirus expressing a small hairpin inhibitory RNA against HuD (shHuD) (17) as well as GFP (SI Appendix, Fig. S2 A-C).…”

Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies

“…Indeed, the Hu proteins have been implicated in mRNA stabilization and RNA turnover 18 , 19 . Among various target mRNAs, HuD has recently been shown to bind, hence stabilizing, the brain-derived neurotrophic factor (BDNF)-coding mRNA 20 . Moreover, neuronal Hu proteins have been shown to bind pre-mRNA species, thus regulating their alternative splicing 21 .…”