title: SIRT1 suppresses self-renewal of adult hippocampal neural stem cells.
abstract: The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience and CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China University of Chinese Academy of Sciences, Shanghai 200031, China cyma@ion.ac.cn mpoo@ion.ac.cn.
authors.forename: Chen-Yan
authors.initials: CY
authors.lastname: Ma
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience and CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Mao-jin
authors.initials: MJ
authors.lastname: Yao
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qi-wei
authors.initials: QW
authors.lastname: Zhai
authors.affiliation: Institute of Zoology, State Key Laboratory of Reproductive Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jian-wei
authors.initials: JW
authors.lastname: Jiao
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience and CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiao-bing
authors.initials: XB
authors.lastname: Yuan
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience and CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China cyma@ion.ac.cn mpoo@ion.ac.cn.
authors.forename: Mu-ming
authors.initials: MM
authors.lastname: Poo
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology*; D003847:Deoxyglucose / Q000009:adverse effects; D005453:Fluorescence; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013629:Tamoxifen
chemical_list: D013629:Tamoxifen; D003847:Deoxyglucose; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D001973:Bromodeoxyuridine
keywords: Adult neurogenesis; SIRT1; Self-renewal