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Author Notes:

To whom correspondence should be addressed. E-mail: yfeng@emory.edu.

Edited by Dale Purves, Duke University Medical Center, Durham, NC, and approved July 15, 2010 (received for review March 9, 2010)

Author contributions: A.G.L. and Y.F. designed research; A.G.L., H.A.I., J.G., D.T., L.K., G.L., M.X., B.F., J.Q.Z., and Y.F. performed research; A.G.L., B.F., and J.Q.Z. analyzed data; and A.G.L., R.D., B.X., B.L., and Y.F. wrote the paper.

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Research Funding:

This study was supported by National Institutes of Health Grants NS056532, 5T32GM008602 (to A.L.), HD061344 (to Y.F.), NS050596 (to B.X.), and NS036604 (to R.D.).

Keywords:

  • alternative 3′UTR
  • tropomyosin-related kinase receptor B
  • hippocampal mossy fiber
  • epilepsy

Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 107, Number 36

Publisher:

, Pages 15945-15950

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Expression of the brain-derived neurotrophic factor (BDNF) is under tight regulation to accommodate its intricate roles in controlling brain function. Transcription of BDNF initiates from multiple promoters in response to distinct stimulation cues. However, regardless which promoter is used, all BDNF transcripts are processed at two alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3′UTR, both encoding the same BDNF protein. Whether and how the two distinct 3′UTRs may differentially regulate BDNF translation in response to neuronal activity changes is an intriguing and challenging question. We report here that the long BDNF 3′UTR is a bona fide cis-acting translation suppressor at rest whereas the short 3′UTR mediates active translation to maintain basal levels of BDNF protein production. Upon neuronal activation, the long BDNF 3′UTR, but not the short 3′UTR, imparts rapid and robust activation of translation from a reporter. Importantly, the endogenous long 3′UTR BDNF mRNA specifically undergoes markedly enhanced polyribosome association in the hippocampus in response to pilocarpine induced-seizure before transcriptional up-regulation of BDNF. Furthermore, BDNF protein level is quickly increased in the hippocampus upon seizure-induced neuronal activation, accompanied by a robust activation of the tropomyosin-related receptor tyrosine kinase B. These observations reveal a mechanism for activity-dependent control of BDNF translation and tropomyosin-related receptor tyrosine kinase B signaling in brain neurons.

Copyright information:

Beginning with articles submitted in Volume 106 (2009) the author(s) retains copyright to individual articles, and the National Academy of Sciences of the United States of America retains an exclusive license to publish these articles and holds copyright to the collective work.

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