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 type2b), 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 p27kip12/2 mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip12/2 mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip12/2 monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip12/2 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 SIGNIFICANCE STATEMENTThe cell cycle associated factor p27kip1 has multiple roles in adult hippocampal neurogenesis, including the control of cell cycle exit. A p27kip1 knockout mouse shows increased proliferation of precursor cells, but (as shown in the study) reduced net neurogenesis: p27kip1 is required for controlled cell cycle exit.

Insulin-like growth factor-1 overexpression increases long-term survival of posttrauma-born hippocampal neurons while inhibiting ectopic migration following traumatic brain injury

“…Acquisition learning may be less sensitive than reversal learning to modulation of hippocampal neurogenesis, as suggested by previous studies demonstrating that an attenuation of adult neurogenesis does not prevent acquisition of the escape platform location during water maze training [20,96]. Brain-injured WT and brain-injured IGF overexpressing mice showed equivalent abilities to learn the location of a hidden platform during the acquisition phase (days 1-2) of RAWM testing.…”

Divide or Commit – Revisiting the Role of Cell Cycle Regulators in Adult Hippocampal Neurogenesis

“…Detailed immunophenotyping revealed that p27 kip1 is expressed by virtually all type 1 NSCs, in the majority of IPCs, in neuroblasts and immature neurons (Qiu et al, 2009; Andreu et al, 2015). Deletion of p27 kip1 increases proliferation of radial aNSC in vivo and in vitro , and Ki67 can be detected only in those few aNSCs that are p27 kip1 -negative, demonstrating a role of p27 kip1 in aNSC quiescence (Qiu et al, 2009; Andreu et al, 2015; Horster et al, 2017). Activation of p27 kip1 mutant NSCs has no effect on the total size of the aNSC pool, indicating that p27 kip1 has no role in the choice between symmetric and asymmetric aNSC divisions (Andreu et al, 2015).…”

“…Recent studies also provided some insight into the role of p27 kip1 in differentiation. P27 kip1 increases upon neuronal differentiation in vitro and in vivo (Varodayan et al, 2009; Andreu et al, 2015; Horster et al, 2017). It becomes induced by proneural genes, such as NeuroD2 or Mash1, suggesting that p27 kip1 is employed by neural determination factors to force differentiation and CC exit (Farah et al, 2000).…”

p27kip1 at the crossroad between actin and microtubule dynamics

“…Consequently, p19/p27 double KO mice showed an abnormal mitotic activity in post-migratory neurons, resulting in a phenotype characterized by bradykinesia, proprioceptive abnormalities, muscle weakness, seizure and death occurring after few weeks from birth, probably because of their inability to feed themselves [30]. More recently, Kempermann et al reported that mice employed in behavioral activities displayed an upregulation of cytoplasmic p27 in the neurogenic zone of the hippocampus, which is devoted to integrating established memory with new pieces of information, suggesting that p27 could also play a role in post-mitotic neurons [31]. Indeed, it is to note that p27 KO mice display a “neurogenesis phenotype” characterized by impaired spatial learning ability if challenged with specific trials requiring hippocampus-dependent strategies [31].…”

“…More recently, Kempermann et al reported that mice employed in behavioral activities displayed an upregulation of cytoplasmic p27 in the neurogenic zone of the hippocampus, which is devoted to integrating established memory with new pieces of information, suggesting that p27 could also play a role in post-mitotic neurons [31]. Indeed, it is to note that p27 KO mice display a “neurogenesis phenotype” characterized by impaired spatial learning ability if challenged with specific trials requiring hippocampus-dependent strategies [31]. Although this phenotype seems to be linked to a cytoplasmic localization of p27, it has not been clearly linked to alterations of the cytoskeleton dynamics.…”