title: Cyclin A2 promotes DNA repair in the brain during both development and aging.
abstract: Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation inCCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice.
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Gygli
authors.affiliation: Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Hamza N
authors.initials: HN
authors.lastname: Gokozan
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Fay P
authors.initials: FP
authors.lastname: Catacutan
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Behiye
authors.initials: B
authors.lastname: Kaya
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Goksel
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Faisal S
authors.initials: FS
authors.lastname: Baig
authors.affiliation: Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Department of Genetics, Harvard Medical School and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.affiliation: Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology, The Ohio State University College of Medicine. Columbus, OH 43210, USA.
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Palanichamy
authors.affiliation: Department of Genetics, Harvard Medical School and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Nelson
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Czeisler
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: José J
authors.initials: JJ
authors.lastname: Otero
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics*; D003213:Conditioning, Psychological / Q000502:physiology; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D018737:Hand Strength / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D012919:Social Behavior; D055153:Stem Cell Niche
chemical_list: D056751:Cyclin A2
keywords: Cyclin A2; DNA repair; mathematical modeling; neural stem cells; ventricular zone/subventricular zone