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Effects of p21 on adult hippocampal neuronal development after irradiation.

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.

SUBMITTER: Li YQ

PROVIDER: S-EPMC6131552 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Effects of p21 on adult hippocampal neuronal development after irradiation.

Li Yu-Qing YQ Wong Chong Shun CS

Cell death discovery 20180718

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 ...[more]

PMID: 30210818

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Project description:BackgroundIron deficiency (ID) compromises the developing nervous system, including the hippocampus, resulting in later-life deficits despite iron repletion. The iron-dependent molecular changes driving these lasting deficits, and the effect of early iron repletion, are incompletely understood. Previous studies have utilized dietary models of maternal-fetal ID anemia (IDA) to address these questions; however, concurrent anemia prevents delineation of the specific role of iron.ObjectiveThe aim of the study was to isolate the effects of developmental ID on adult hippocampal gene expression and to determine if iron repletion reverses these effects in a mouse model of nonanemic hippocampal neuronal ID.MethodsNonanemic, hippocampus-specific neuronal ID was generated by using a Tet-OFF dominant negative transferrin receptor (DN-TFR1) mouse model that impairs cellular iron uptake. Hippocampal ID was reversed with doxycycline at postnatal day 21 (P21) in a subset of mice to create 2 experimental groups, chronically iron-deficient and formerly iron-deficient mice, which were compared with their respective doxycycline-treated and untreated iron-sufficient controls. RNA from adult male hippocampi was sequenced. Paired-end reads were analyzed for differential expression. Differentially expressed genes were analyzed in Ingenuity Pathway Analysis.ResultsA total of 346 genes were differentially expressed in adult, chronically iron-deficient hippocampi compared with controls. ID dysregulated genes in critical neurodevelopmental pathways, including axonal guidance, CDK5, Ephrin receptor, Rac, and Neurotrophin/Trk signaling. Iron repletion at P21 normalized adult hippocampal expression of 198 genes; however, genes involved in cAMP response element-binding protein (CREB) signaling, neurocognition, and neurologic disease remained dysregulated in adulthood.ConclusionsChronic ID during development, independent of anemia, alters the adult mouse hippocampal transcriptome. Restoring iron status during a known critical period of hippocampal neurodevelopment incompletely normalized these changes, suggesting a need for additional studies to identify the most effective timeline for iron therapy, and adjunctive treatments that can fully restore ID-induced molecular changes, particularly in human populations in whom chronic ID is endemic.

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Effects of p21 on adult hippocampal neuronal development after irradiation.

Publications

Effects of p21 on adult hippocampal neuronal development after irradiation.

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