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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00062

Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) In Neurons And Promotes ATF4-Dependent Induction Of Sesn2

 Lloyd A. Greene1*, Jin Liu1,  Fatou Amar1, Carlo Corona1,  Raphaella W. So1, Stuart J. Andrews1, Peter L. Nagy1 and  Michael L. Shelanski1
  • 1Pathology and Cell Biology, Columbia University, United States

Activating Transcription Factor 4 (ATF4) plays important physiologic roles in the brain including regulation of learning and memory as well as neuronal survival and death. Yet, outside of translational regulation by the eIF2-dependent stress response pathway, there is little information about how its levels are controlled in neurons. Here, we show that brain-derived neurotrophic factor (BDNF) promotes a rapid and sustained increase in neuronal ATF4 transcripts and protein levels. This increase is dependent on TrkB signaling, but independent of levels of phosphorylated eIF2. The elevation in ATF4 protein occurs both in nuclei and processes. Transcriptome analysis revealed that ATF4 mediates BDNF-promoted induction of Sesn2 which encodes Sestrin2, a protector against oxidative and genotoxic stresses and a mTor complex 1 inhibitor. In contrast, BDNF-elevated ATF4 did not affect expression of a number of other known ATF4 targets including several with pro-apoptotic activity. The capacity of BDNF to elevate neuronal ATF4 may thus represent a means to maintain this transcription factor at levels that provide neuroprotection and optimal brain function without risk of triggering neurodegeneration.

Keywords: Brain-derived neurotrophic factor (BDNF), Transcription Factors, Neurons, gene regulation, neurotrophins, Activating Transcription Factor 4, Sestrin2

Received: 06 Nov 2017; Accepted: 14 Feb 2018.

Edited by:

Andrei Surguchov, University of Kansas Medical Center, United States

Reviewed by:

Christine Gall, University of California, Irvine, United States
Brittney Yegla, University of Florida, United States
Jozsef Dudas, Innsbruck Medical University, Austria  

Copyright: © 2018 Greene, Liu, Amar, Corona, So, Andrews, Nagy and Shelanski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Lloyd A. Greene, Columbia University, Pathology and Cell Biology, 630 W. 168th Street, New York City, 10032, NY, United States,