Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis - PubMed (original) (raw)
Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis
Dengke K Ma et al. Science. 2009.
Abstract
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 brain-derived neurotrophic factor and fibroblast growth factor. 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.
Figures
Fig. 1
Activity-induced neuronal Gadd45b expression. (A) Quantitative polymerase chain reaction (Q-PCR) analysis of ECT-induced expression of Gadd45a, Gadd45b, and Gadd45g in the adult dentate gyrus after a single ECT. (B) Sample images of Gadd45b in situ hybridization of the adult hippocampus after ECT. Scale bar: 0.5 mm. (C and D) Gadd45 induction in the dentate gyrus after 1 hour of spatial exploration of a novel environment. (C) A summary from Q-PCR analysis. (D) Sample confocal images of Gadd45b in situ hybridization, and 4′,6-diamidino-2-phenylindole (DAPI) and Arc immunostaining. Most of the Gadd45b-positive cells (open and closed arrowheads) were Arc-positive (closed arrowheads). Scale bar: 50 μm. (E) NMDAR-dependent induction of Gadd45b, Arc, and Homer1 in the adult dentate gyrus at 1 hour after ECT. The NMDAR antagonist CPP was injected intraperitoneally at 1 hour before ECT (10 mg per kg of body weight). Values represent mean ± SEM [n = 4 animals; *P < 0.01, analysis of variance (ANOVA)].
Fig. 2
Essential role of Gadd45b in activity-induced proliferation of adult neural progenitors. (A) Sample projected confocal images of BrdU immunostaining (red) and DAPI (blue). Scale bar: 50 μm. (B) Summary of stereological quantification of BrdU+ cells in the dentate gyrus. Values represent mean ± SEM (n = 4 or 5 animals as indicated; *P < 0.01, ANOVA).
Fig. 3
Essential role of Gadd45b in activity-induced dendritic development of newborn neurons in the adult brain. (A) Sample projected Z-series confocal images of GFP+ dentate granule cells at 14 days after viral labeling. Scale bar: 50 μm. (B) Quantification of the total dendritic length of GFP+ dentate granule cells. Values represent mean ± SEM (n = 23 to 45 neurons for each condition; *P < 0.01, ANOVA). (C) Analysis of dendritic complexity of the same group of cells as in (B). Values represent mean ± SEM (*P < 0.01, Student's t test).
Fig. 4
Essential role of Gadd45b in activity-induced specific DNA demethylation and gene expression in the adult dentate gyrus. (A and B) Bisulfite sequencing analysis of adult dentate gyrus tissue before or at 4 hours after ECT. (A) A schematic diagram of the genomic region subjected to analysis and a summary of methylation frequency at individual CpG sites. (B) A summary of mean DNA methylation levels of individual alleles. Values represent mean ± SEM (n = 10 to 15 reads; **P < 0.01, *_P_ < 0.05, #P > 0.1, ANOVA; exact P values are given in table S2). (C) Methylation-specific PCR analysis from the dentate gyrus of WT mice after one or two ECTs (“24+4”: 4 hours after two ECTs at 24 hours apart) or 7 days after lentivirus-mediated expression of Gadd45b-GFP or GFP alone without ECT. Primers are specific for methylated (M) and unmethylated alleles (UM) of the Fgf-1B promoter, or for bisulfite sequencing without CpGs (Input). (D) Summary of the mRNA and protein expression in the dentate gyrus of adult Gadd45b WT and KO mice at 4 hours after ECT and sham controls. Values represent mean ± SEM (n = 4 animals; *P < 0.01, ANOVA).
Comment in
- Waiting for Gadd45b.
Parent JM. Parent JM. Epilepsy Curr. 2009 Nov-Dec;9(6):170-2. doi: 10.1111/j.1535-7511.2009.01332.x. Epilepsy Curr. 2009. PMID: 19936135 Free PMC article. No abstract available.
Similar articles
- Status epilepticus induced Gadd45b is required for augmented dentate neurogenesis.
Xiao XL, Wu XL, Yang PB, Hu HB, Chen Y, Min-Li, Si KW, Wu F, Liu JX. Xiao XL, et al. Stem Cell Res. 2020 Dec;49:102102. doi: 10.1016/j.scr.2020.102102. Epub 2020 Nov 30. Stem Cell Res. 2020. PMID: 33279798 - Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis.
Wu H, Sun YE. Wu H, et al. Sci Signal. 2009 Mar 31;2(64):pe17. doi: 10.1126/scisignal.264pe17. Sci Signal. 2009. PMID: 19336837 - Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity.
Sultan FA, Wang J, Tront J, Liebermann DA, Sweatt JD. Sultan FA, et al. J Neurosci. 2012 Nov 28;32(48):17059-66. doi: 10.1523/JNEUROSCI.1747-12.2012. J Neurosci. 2012. PMID: 23197699 Free PMC article. - Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind.
Hsieh J, Eisch AJ. Hsieh J, et al. Neurobiol Dis. 2010 Jul;39(1):73-84. doi: 10.1016/j.nbd.2010.01.008. Epub 2010 Jan 28. Neurobiol Dis. 2010. PMID: 20114075 Free PMC article. Review. - [Progress of adult hippocampus neurogenesis].
Fan XT, Cai WQ. Fan XT, et al. Sheng Li Ke Xue Jin Zhan. 2003 Jul;34(3):259-62. Sheng Li Ke Xue Jin Zhan. 2003. PMID: 14628477 Review. Chinese. No abstract available.
Cited by
- The epigenetic signatures of opioid addiction and physical dependence are prevented by D-cysteine ethyl ester and betaine.
McDonough J, Singhal NK, Getsy PM, Knies K, Knauss ZT, Mueller D, Bates JN, Damron DS, Lewis SJ. McDonough J, et al. Front Pharmacol. 2024 Aug 30;15:1416701. doi: 10.3389/fphar.2024.1416701. eCollection 2024. Front Pharmacol. 2024. PMID: 39281282 Free PMC article. - Can exercise benefits be harnessed with drugs? A new way to combat neurodegenerative diseases by boosting neurogenesis.
Zhao R. Zhao R. Transl Neurodegener. 2024 Jul 25;13(1):36. doi: 10.1186/s40035-024-00428-7. Transl Neurodegener. 2024. PMID: 39049102 Free PMC article. Review. - Temporal changes in mouse hippocampus transcriptome after pilocarpine-induced seizures.
Popova EY, Kawasawa YI, Leung M, Barnstable CJ. Popova EY, et al. Front Neurosci. 2024 Jul 8;18:1384805. doi: 10.3389/fnins.2024.1384805. eCollection 2024. Front Neurosci. 2024. PMID: 39040630 Free PMC article. - Advances in the role of the GADD45 family in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders.
Huang M, Wang J, Liu W, Zhou H. Huang M, et al. Front Neurosci. 2024 Jan 25;18:1349409. doi: 10.3389/fnins.2024.1349409. eCollection 2024. Front Neurosci. 2024. PMID: 38332860 Free PMC article. Review. - Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin.
Jiang WI, De Belly H, Wang B, Wong A, Kim M, Oh F, DeGeorge J, Huang X, Guang S, Weiner OD, Ma DK. Jiang WI, et al. Sci Adv. 2024 Jan 26;10(4):eadj3880. doi: 10.1126/sciadv.adj3880. Epub 2024 Jan 24. Sci Adv. 2024. PMID: 38266092 Free PMC article.
References
- Kempermann G, van Praag H, Gage FH. Prog Brain Res. 2000;127:35. - PubMed
- Ming GL, Song H. Annu Rev Neurosci. 2005;28:223. - PubMed
- Madsen TM, et al. Biol Psychiatry. 2000;47:1043. - PubMed
- Jaenisch R, Bird A. Nat Genet. 2003;33(suppl):245. - PubMed
- Materials and methods and supporting data are available on Science Online
Publication types
MeSH terms
Substances
Grants and funding
- R01 HD069184/HD/NICHD NIH HHS/United States
- R01 NS048271/NS/NINDS NIH HHS/United States
- R01 NS048271-05/NS/NINDS NIH HHS/United States
- HHMI/Howard Hughes Medical Institute/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases