title: p27kip1 Is Required for Functionally Relevant Adult Hippocampal Neurogenesis in Mice.
abstract: We asked whether cell-cycle associated protein p27kip1 might be involved in the transition of precursor cells to postmitotic maturation in adult hippocampal neurogenesis. p27kip1 was expressed throughout the dentate gyrus with a strong nuclear expression in early postmitotic, calretinin-positive neurons and neuronally determined progenitor cells (type-3 and some type-2b), lower or absent expression in radial glia-like precursor cells (type-1) and type-2a cells and essentially no expression in granule cells. This suggested a transitory role in late proliferative and early postmitotic phases of neurogenesis. Inconsistent with a role limited to cell cycle arrest the acute stimuli, voluntary wheel running (RUN), environmental enrichment (ENR) and kainate-induced seizures increased p27kip1 expressing cells. Sequential short-term combination of RUN and ENR yielded more p27kip1 cells than either stimulus alone, indicating an additive effect. In vitro, p27kip1 was lowly expressed by proliferating precursor cells but increased upon differentiation. In p27kip1-/- mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip1-/- mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip1-/- monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip1-/- mice learned the task but were specifically impaired in the reversal phase explainable by the decrease in adult neurogenesis. We conclude that p27kip1 is involved in the decisive step around cell-cycle exit and plays an important role in activity-regulated and functionally relevant adult hippocampal neurogenesis. Stem Cells 2017;35:787-799.
authors: CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors: Henrik
authors: H
authors: Hörster
authors: German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany.
authors: Alexander
authors: A
authors: Garthe
authors: CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors: Tara L
authors: TL
authors: Walker
authors: CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
authors: Muhammad
authors: M
authors: Ichwan
authors: Department of Neurology, Charité University Medicine Berlin, Berlin, Germany.
authors: Barbara
authors: B
authors: Steiner
authors: Adult Neurogenesis Group, Institute of Developmental Genetics, Helmholtz Center Munich, Oberschleißheim, Germany.
authors: Muhammad Amir
authors: MA
authors: Khan
authors: Institut für Biochemie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Dieter Chichung
authors: DC
authors: Lie
authors: CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.|German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany.
authors: Zeina
authors: Z
authors: Nicola
authors: Laboratory of Neurogenesis, Division of Clinical Investigations, National Institute of Psychiatry "Ramón de la Fuente Muñiz", México, D.F, México.
authors: Gerardo
authors: G
authors: Ramirez-Rodriguez
authors: German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany.
authors: Gerd
authors: G
authors: Kempermann
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D065853:Spatial Learning
chemical_list: D015415:Biomarkers; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Cell cycle; Granule cells; Hippocampus; Learning; Plasticity; Stem cells