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Published Online January 1, 2009
Science DOI: 10.1126/science.1166859

Reports

Submitted on October 6, 2008
Accepted on December 16, 2008

Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis

Dengke K. Ma 1{dagger}*, Mi-Hyeon Jang 2{dagger}, Junjie U. Guo 1, Yasuji Kitabatake 2, Min-lin Chang 2, Nattapol Pow-anpongkul 3, Richard A. Flavell 4, Binfeng Lu 5, Guo-li Ming 6, Hongjun Song 6*

1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
2 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.; Department of Neurology, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
3 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
4 Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
5 Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
6 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.; Department of Neurology, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed.
Dengke K. Ma , E-mail: dma2{at}jhmi.edu
Hongjun Song , E-mail: shongju1{at}jhmi.edu

{dagger}These authors contributed equally to this work.

The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here, we identify Gadd45b as a neural activity–induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity–induced proliferation of neural progenitors and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of corresponding genes critical for adult neurogenesis, including BDNF and FGF. Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain.


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