The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein
The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein
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DOI：
10.1038/cdd.2008.95
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发表时间：
2008-10-01
影响因子：
12.4
通讯作者：
Meucci, O.
中科院分区：
文献类型：
--
作者：
Khan, M. Z.;Brandimarti, R.;Meucci, O.
有丝分裂后的神经元需要控制其细胞周期以存活并维持分化状态。本研究旨在验证趋化因子CXCL 12通过促进Rb功能调节神经元存活和分化的假设，如先前的研究所示，CXCL 12保护神经元免受Rb丢失诱导的凋亡。为此，研究了CXCL 12对Rb表达和转录活性的影响以及Rb在CXCL 12诱导的神经元存活中的作用。CXCL 12增加大鼠皮层神经元Rb蛋白和RNA水平。该趋化因子还刺激在这些神经元中表达的外源性Rb启动子，并抵消由E2 F1过表达诱导的Rb启动子的抑制。此外，CXCL 12作为转录抑制物刺激Rb活性。CXCL 12的作用是由其特异性受体CXCR 4介导的，并且不需要胶质细胞的存在。最后，shRNA研究表明，Rb的表达是至关重要的神经保护活性的CXCL 12所示的NMDA神经毒性试验。这些发现表明，在成熟的CNS中适当的CXCR 4刺激可以防止Rb-E2 F通路的损伤并支持神经元存活。这对于在生理条件下维持CNS完整性和防止许多神经变性和神经炎性病症典型的神经元损伤和损失是重要的。
Postmitotic neurons need to keep their cell cycle under control to survive and maintain a differentiated state. This study aims to test the hypothesis that the chemokine CXCL12 regulates neuronal survival and differentiation by promoting Rb function, as suggested by previous studies showing that CXCL12 protects neurons from apoptosis induced by Rb loss. To this end, the effect of CXCL12 on Rb expression and transcriptional activity and the role of Rb in CXCL12-induced neuronal survival were studied. CXCL12 increases Rb protein and RNA levels in rat cortical neurons. The chemokine also stimulates an exogenous Rb promoter expressed in these neurons and counteracts the inhibition of the Rb promoter induced by E2F1 overexpression. Furthermore CXCL12 stimulates Rb activity as a transcription repressor. The effects of CXCL12 are mediated by its specific receptor CXCR4, and do not require the presence of glia. Finally, shRNA studies show that Rb expression is crucial to the neuroprotective activity of CXCL12 as indicated by NMDA-neurotoxicity assays. These findings suggest that proper CXCR4 stimulation in the mature CNS can prevent impairment of the Rb-E2F pathway and support neuronal survival. This is important to maintain CNS integrity in physiological conditions and prevent neuronal injury and loss typical of many neurodegenerative and neuroinflammatory conditions.