Abstract
Inhibition of hippocampal neurogenesis is implicated in neurocognitive impairment after cranial irradiation. We recently demonstrated that disruption of neuronal development after DNA damage was regulated by p53. The cyclin-dependent kinase inhibitor 1 or p21, a downstream effector p53, mediates cell cycle arrest in response to DNA damage. There is evidence that p21 negatively regulates proliferation of neural progenitors (NPCs). Here we characterized the effects of p21 on disruption of neuronal development in the hippocampal dentate gyrus after irradiation. We irradiated young adult mice wild type (+/+) or knockout (−/−) of the Cdkn1a (p21) gene, and used different bromodeoxyuridine (BrdU) paradigms for cell fate mapping. The acute apoptotic response of NPCs in the subgranular zone of the dentate gyrus was independent of p21 after irradiation. In nonirradiated mice, p21 knockout resulted in an increase in neuroblast proliferation and neurogenesis. At 9 weeks after 5Gy, NPCs in the subgranular zone demonstrated increased p21 expression. Loss of newborn type-1 cells and disruption of hippocampal neurogenesis was evident at 9 weeks after irradiation, and these effects were independent of p21 genotype status. Within the developmental milestones of NPCs, irradiation resulted in loss of early intermediate NPCs (type-2a cells) in wild-type mice, whereas the principal effect of irradiation with p21 loss was culling of proliferating late intermediate (type-2b cells) and neuroblasts. These results suggest that p21 exerts differential effects on cell fate of NPCs after irradiation. p21 may serve to protect proliferating late NPCs but does not alter the ultimate inhibition of new neuron production after DNA damage.
Highlights
Multipotent neural stem cells and/or neural progenitor cells (NPCs) are present in the adult mammalian central nervous system
Apoptosis of neural progenitors after irradiation is independent of p21
Inhibition of hippocampal neurogenesis is implicated in neurocognitive decline following radiation treatment for brain tumors[18]
Summary
Multipotent neural stem cells and/or neural progenitor cells (NPCs) are present in the adult mammalian central nervous system. In the adult mammalian brain, the dentate gyrus of the hippocampus represents an area where NPCs continue to generate new neurons which become integrated into the neuronal circuitry[1,2]. Many physiologic conditions such as an enriched environment and exercise have been reported to result in enhanced adult neurogenesis[3]. Neuronal development in the adult hippocampus is disrupted in various pathologic conditions and brain injuries[1,2] including after ionizing radiation[4]. How DNA damage following ionizing radiation leads to impaired neuronal development in the adult hippocampus remains unclear[7]
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