Research Paper Volume 8, Issue 7 pp 1540—1570
Cyclin A2 promotes DNA repair in the brain during both development and aging
- 1 Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- 2 Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA
- 3 Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- 4 Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA
- 5 Department of Genetics, Harvard Medical School and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA
- 6 Department of Radiation Oncology, The Ohio State University College of Medicine. Columbus, OH 43210, USA
Received: April 26, 2016 Accepted: July 13, 2016 Published: July 17, 2016
https://doi.org/10.18632/aging.100990How to Cite
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 in CCNA2-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.