title: The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.
abstract: The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.
authors.affiliation: Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bouchard-Cannon
authors.affiliation: Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mendoza-Viveros
authors.affiliation: Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yuen
authors.affiliation: Ottawa Institute of Systems Biology, Department of Cellular and Molecular Medicine, and Department of Physics, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. Electronic address: mkaern@uottawa.ca.
authors.forename: Mads
authors.initials: M
authors.lastname: Kærn
authors.affiliation: Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada. Electronic address: haiying.cheng@utoronto.ca.
authors.forename: Hai-Ying M
authors.initials: HY
authors.lastname: Cheng
mesh_terms: D056930:ARNTL Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D057906:Circadian Clocks / Q000235:genetics*; D056741:Cyclin D / Q000037:antagonists & inhibitors; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D056950:Period Circadian Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056741:Cyclin D; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6