Stem Cell Reports
Volume 10, Issue 6, 5 June 2018, Pages 1721-1733
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Article
INK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice

https://doi.org/10.1016/j.stemcr.2018.03.025Get rights and content
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Highlights

  • INK4a/ARF expression is induced in neural progenitor cells following exposure to IR

  • Absence of INK4a/ARF expression favors neurogenesis in the irradiated brain

  • Genetic ablation of p16INK4a-expressing cells does not restore neurogenesis

  • IR-induced activation of the microglia is dependent on p53 but not INK4a/ARF expression

Summary

Brain neurogenesis is severely impaired following exposure to ionizing radiation (IR). We and others have shown that the expression of the tumor suppressor gene p16INK4a is increased in tissues exposed to IR and thus hypothesized that its expression could limit neurogenesis in the irradiated brain. Here, we found that exposure to IR leads to persistent DNA damage and the expression of p16INK4a in the hippocampus and subventricular zone regions. This was accompanied by a decline in neurogenesis, as determined by doublecortin expression and bromodeoxyuridine incorporation, an effect partially restored in Ink4a/arf-null mice. Increased neurogenesis in the absence of INK4a/ARF expression was independent of apoptosis and activation of the microglia. Moreover, treatment of irradiated mice with a superoxide dismutase mimetic or clearance of p16INK4a-expressing cells using mouse genetics failed to increase neurogenesis. In conclusion, our results suggest that IR-induced p16INK4a expression is a mechanism that limits neurogenesis.

Keywords

INK4a/ARF
neurogenesis
irradiation
p53
senescence
DNA damage

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