Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain
| Autor: | Aryn Schloemer, Kevin A. Burns, Frank R. Sharp, Michael T. Williams, Pasko Rakic, Richard A. Flavell, Charles V. Vorhees, Wei Lan Weng, Chia-Yi Kuan, Aigang Lu, Roger I. Davis, Kenneth I. Strauss |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Excitotoxicity Apoptosis Mice Inbred Strains medicine.disease_cause Hippocampus Article S Phase Rats Sprague-Dawley Mice chemistry.chemical_compound Excitatory Amino Acid Agonists In Situ Nick-End Labeling medicine Animals Neurons Kainic Acid TUNEL assay biology DNA synthesis General Neuroscience Neurogenesis Age Factors Retinoblastoma protein Brain Adrenalectomy DNA Cell cycle Molecular biology Rats Mice Inbred C57BL Bromodeoxyuridine nervous system chemistry Brain Injuries Hypoxia-Ischemia Brain biology.protein NeuN |
| Zdroj: | The Journal of Neuroscience. 24:10763-10772 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3883-04.2004 |
| Popis: | Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G1/S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G1/S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU- and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU+neurons, labeled shortly after hypoxia-ischemia, persist for >5 d but eventually disappear by 28 d. Before disappearing, these BrdU+/NeuN+/TUNEL+neurons express the proliferating cell marker Ki67, lose the G1-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G1/S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G1/S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis. |
| Databáze: | OpenAIRE |
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