Involvement of the 3′‐untranslated region of the brain‐derived neurotrophic factor gene in activity‐dependent mRNA stabilization

J. Neurochem. (2010) 115, 1222-1233. ABSTRACT: Although gene transcription is controlled by neuronal activity, little is known about post‐transcriptional regulation in neurons. Using cultured neurons, we found that the half‐life of immediate‐early gene transcripts is prolonged or shortened by membrane depolarization. Focusing on the activity‐dependent stabilization of brain‐derived neurotrophic factor (BDNF) mRNA, we constructed a series of plasmids, in which the short 3′‐untranslated region (3′‐UTR) of the BDNF gene was fused to the firefly luciferase gene, and found that the 3′‐UTR prevented destabilization of luciferase mRNA through Ca²⁺ signals evoked via depolarization. No such prevention was observed with the simian virus 40 late poly(A) site. The pre‐mRNA covering the entire short 3′‐UTR, where multiple poly(A) sites including novel ones are located, was stabilized. Deletion analyses of 3′‐UTR revealed a core region (about 130 bases long) and a complementary region to be responsible for the prevention, well consistent with the formation of an extended stem‐loop RNA structure and the production of poly(A) mRNAs. Thus, the mRNA stability is activity‐dependently controlled in neurons and distinct regions of the 3′‐UTR of BDNF mRNA are involved in stabilizing mRNA in response to Ca²⁺ signals, suggesting a primary role of the RNA secondary structure affecting the availability of poly(A) sites in activity‐dependent mRNA stabilization.