Neural Precursor Cell Proliferation Is Disrupted Through Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Neural Precursor Cell Proliferation Is Disrupted Through Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
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DOI：
10.1089/scd.2009.0529
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发表时间：
2011-02-01
影响因子：
4
通讯作者：
Opanashuk, Lisa A.
中科院分区：
文献类型：
--
作者：
Latchney, Sarah E.;Lioy, Daniel T.;Opanashuk, Lisa A.
神经发生涉及多能神经上皮干细胞的增殖，随后在胚胎期分化为谱系限制的神经前体细胞（NPC）。有趣的是，这些祖细胞表达稳定水平的芳烃受体（AhR），一种配体激活的转录因子，调节对生长调节和外源性代谢重要的基因的表达。在结合2，3，7，8-四氯二苯并-p-二恶英（TCDD）时，普遍存在的环境污染物和有效的AhR配体AhR被激活并破坏基因表达模式以产生细胞毒性。由于AhR在神经发生的关键增殖阶段广泛分布于脑中，因此可以想象AhR参与了NPC的扩张。因此，本研究验证了TCDD激活AhR破坏调节NPC增殖的信号传导事件的假设。C17.2 NPC细胞系作为模型系统，用于（1）评估NPC是否是TCDD诱导的神经毒性的靶点，以及（2）表征TCDD对NPC增殖的影响。我们证明，C17.2 NPC表达一个完整的AhR信号通路，成为TCDD暴露后转录活跃。3 H-胸苷和亚甲蓝还原试验表明，TCDD以浓度依赖的方式抑制NPC增殖，而不损失细胞活力。流式细胞仪分析细胞周期分布显示，TCDD诱导的生长停滞的结果从受损的G1到S细胞周期的转换。此外，TCDD暴露改变p27（kip 1）和细胞周期蛋白D1细胞周期调控蛋白的表达水平与G1期阻滞一致。从胚胎小鼠腹侧前脑分离的初级NPC的初步研究表明，TCDD通过G1期阻滞降低细胞增殖，证实了我们在C17.2细胞系中的发现。总之，这些观察结果表明，在神经发生过程中TCDD对AhR的不适当或持续激活可能会干扰调节神经上皮干细胞/NPC增殖的信号通路，这可能会对大脑中的最终细胞数量产生不利影响，并导致功能障碍。
Neurogenesis involves the proliferation of multipotent neuroepithelial stem cells followed by differentiation into lineage-restricted neural precursor cells (NPCs) during the embryonic period. Interestingly, these progenitor cells express robust levels of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates expression of genes important for growth regulation, and xenobiotic metabolism. Upon binding 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), a pervasive environmental contaminant and potent AhR ligand, AhR, is activated and disrupts gene expression patterns to produce cellular toxicity. Because of its widespread distribution in the brain during critical proliferative phases of neurogenesis, it is conceivable that AhR participates in NPC expansion. Therefore, this study tested the hypothesis that AhR activation by TCDD disrupts signaling events that regulate NPC proliferation. The C17.2 NPC line served as a model system to (1) assess whether NPCs are targets for TCDD-induced neurotoxicity and (2) characterize the effects of TCDD on NPC proliferation. We demonstrated that C17.2 NPCs express an intact AhR signaling pathway that becomes transcriptionally active after TCDD exposure. 3 H-thymidine and alamar blue reduction assays indicated that TCDD suppresses NPC proliferation in a concentration-dependent manner without the loss of cell viability. Cell cycle distribution analysis by flow cytometry revealed that TCDD-induced growth arrest results from an impaired G1 to S cell cycle transition. Moreover, TCDD exposure altered p27(kip1) and cyclin D1 cell cycle regulatory protein expression levels consistent with a G1 phase arrest. Initial studies in primary NPCs isolated from the ventral forebrain of embryonic mice demonstrated that TCDD reduced cell proliferation through a G1 phase arrest, corroborating our findings in the C17.2 cell line. Together, these observations suggest that the inappropriate or sustained activation of AhR by TCDD during neurogenesis can interfere with signaling pathways that regulate neuroepithelial stem cell/NPC proliferation, which could adversely impact final cell number in the brain and lead to functional impairments.