Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain
Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain
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DOI：
10.1523/jneurosci.3883-04.2004
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发表时间：
2004-11-24
影响因子：
5.3
通讯作者：
Rakic, P
中科院分区：
文献类型：
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作者：
Kuan, CY;Schloemer, AJ;Rakic, P
最近的研究表明，有丝分裂后的神经元可以重新进入细胞周期，作为脑损伤后细胞凋亡的前奏。然而，大多数垂死的神经元不能通过G（1）/S期检查点来恢复DNA合成。触发DNA合成失败的特定因素尚未得到表征。在这里，我们表明，缺氧和缺血的组合诱导成年啮齿动物神经元恢复DNA合成所示的溴脱氧尿苷（BrdU）和G（1）/S期细胞周期转换标记物的表达。缺氧缺血后，大多数的BrdU和神经元核（NeuN）的免疫反应细胞也是末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记（TUNEL）染色，表明他们进行凋亡。在缺氧缺血后不久标记的BrdU（+）神经元持续超过5 d，但最终在28 d消失。在消失之前，这些BrdU（+）/NeuN（+）/TUNEL+神经元表达增殖细胞标记Ki 67，失去G（1）期细胞周期蛋白依赖性激酶（CDK）抑制剂p16 INK 4和p27 Kip 1，并显示诱导晚期G（1）/S期CDK 2活性和视网膜母细胞瘤蛋白磷酸化。这与红藻氨酸兴奋性毒性和创伤性脑损伤形成对比，后者产生TUNEL阳性神经元，而没有DNA合成或G（1）/S期细胞周期转换的证据。这些结果表明，缺氧缺血触发神经元重新进入细胞周期，并恢复脑内与缺氧相关的DNA合成。我们的数据还表明，脑损伤后的神经发生的演示不仅需要BrdU摄取和成熟的神经元标记物，但也有证据表明没有凋亡标记物。操纵缺氧缺血和可能的神经退行性疾病中发生的异常脑白质变性相关DNA合成可以促进神经元存活和神经发生。
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 G(1)/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 G(1)/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 G(1)-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G(1)/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 G(1)/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.