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首页> 外文期刊>Molecular and Cellular Biology >Neuropilin-1 Is a Direct Target of the Transcription Factor E2F1 during Cerebral Ischemia-Induced Neuronal Death In Vivo
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Neuropilin-1 Is a Direct Target of the Transcription Factor E2F1 during Cerebral Ischemia-Induced Neuronal Death In Vivo

机译：Neuropilin-1是在脑缺血诱导的体内神经元死亡过程中转录因子E2F1的直接目标。

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The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1+/+ and E2F1?/? mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1?/? neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1?/? neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.
机译：核转录因子E2F1在调节神经元对兴奋性毒性和脑缺血的死亡中起重要作用。在这里，通过使用定制的高密度DNA微阵列比较E2F1 + / + 和E2F1 ？/？小鼠的大脑皮层中的基因表达，我们确定了一组推定的E2F1可能负责缺血诱导的E2F1依赖性神经元死亡的靶基因。基于（i）NRP-1启动子序列包含E2F1结合位点这一事实，证实神经纤维蛋白1（NRP-1）是信号量3A介导的轴突生长锥塌陷和收缩的受体，是E2F1的直接靶标。 （ii）替换E2F1基因后，重新激活E2F1 ？/？神经元中NRP-1的表达;（iii）在荧光素酶报告基因分析中，E2F1激活NRP-1启动子，（（iv ）电泳迁移率凝胶位移分析证实了NRP-1启动子中存在E2F结合序列，并且（v）染色质免疫沉淀试验表明E2F1直接与内源性NRP-1启动子结合。有趣的是，脑缺血诱导的E2F1与NRP-1启动子结合的时间诱导与NRP-1 mRNA的时间诱导谱相关，证实E2F1在脑缺血过程中正调控NRP-1。功能分析还表明，NRP-1受体在E2F1 // 神经元中的表达极低，这导致对信号量3A引起的轴突缩短和神经元死亡的反应减弱。 NRP-1选择性肽抑制剂可提供抗氧葡萄糖剥夺的神经保护作用。综上所述，这些发现支持了一种模型，其中E2F1靶向NRP-1以调节对脑缺血的轴突损伤和神经元死亡。

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