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.