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首页> 外文期刊>Journal of neuroinflammation >Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways
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Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

机译：神经元c-Abl激活导致细胞周期和干扰素信号传导途径的诱导

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Background Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. Methods To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. Results Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. Conclusions Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain.
机译：活性c-Abl在AblPP / tTA小鼠的成年小鼠前脑神经元中的表达导致严重的神经变性，特别是在海马CA1区。在发生神经元丧失之前，并伴有大量的小胶质细胞增生和星形胶质细胞增多症。相比之下，虽然蛋白表达和激酶活性与AblPP / tTA小鼠相似，但在小鼠前脑神经元（ArgPP / tTA小鼠）中表达组成性活性Arg（Abl相关基因）不会引起可检测的神经元丢失或胶质增生。 。方法为了阐明c-Abl引起的神经元丢失和神经胶质细胞增生的机制，对AblPP / tTA小鼠前脑进行明显的基因表达分析。通过定量逆转录PCR，免疫印迹和溴脱氧尿苷（BrdU）标记以及免疫细胞化学验证了基因表达研究的部分结果。结果在2周内具有c-Abl表达的AblPP / tTA小鼠中，上调的两个主要途径是细胞周期和干扰素信号传导。但是，只有干扰素信号通路基因的表达在c-Abl诱导4周后仍保持升高。 BrdU掺入研究证实，尽管在c-Abl诱导2周后AblPP / tTA小鼠的细胞周期通路被上调，但该通路的解剖定位与AblPP / tTA小鼠先前的病理学不一致。 STAT1的表达和激活增加，这是干扰素信号传导和干扰素诱导的神经元兴奋性毒性的已知成分，是AblPP / tTA小鼠中c-Abl激活的早期结果，并发生在海马CA1区，该区域继续发展严重的神经退行性病变和神经炎症。有趣的是，没有检测到干扰素自身的基因表达上调。结论我们的数据表明，干扰素信号传导途径可能在神经元中c-Abl表达引起的病理过程中起作用，并且AblPP / tTA小鼠可能是研究无菌炎症和干扰素信号传导对神经元影响的理想模型。脑。

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