Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways.
Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways.
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DOI：
10.1186/1742-2094-9-208
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发表时间：
2012-08-31
影响因子：
9.3
通讯作者：
Davies P
中科院分区：
文献类型：
--
作者：
Schlatterer SD;Suh HS;Conejero-Goldberg C;Chen S;Acker CM;Lee SC;Davies P
表达活性c-Abl在成年小鼠前脑神经元中的ESTPP/tTA小鼠导致严重的神经变性，特别是在海马CA 1区。神经元损失之前，并伴有大量的小胶质细胞增生和星形细胞增生。相比之下，在小鼠前脑神经元（ArgPP/tTA小鼠）的组成型活性精氨酸（精氨酸相关基因）的表达没有引起可检测到的神经元丢失或神经胶质增生，尽管蛋白质表达和激酶活性处于与ArgPP/tTA小鼠相似的水平。为了开始阐明c-Abl诱导的神经元损失和神经胶质增生的机制，在明显病理学发展之前进行了TCPP/tTA小鼠前脑的基因表达分析。从基因表达研究中选择的结果进行了验证与定量逆转录PCR，免疫印迹和溴脱氧尿苷（BrdU）标记，并通过免疫细胞化学。在c-Abl表达2周的TCPP/tTA小鼠中上调的两个最重要的途径是细胞周期和干扰素信号传导。然而，只有干扰素信号通路基因的表达在c-Abl诱导4周时保持升高。BrdU掺入研究证实，虽然在c-Abl诱导2周时，细胞周期途径在TCPP/tTA小鼠中上调，但该途径的解剖学定位与TCPP/tTA小鼠中观察到的先前病理学不一致。STAT 1（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组分）的表达和活化增加是C-Abl活化在TCPP/tTA小鼠中的早期结果，并且发生在海马体的CA 1区域，该区域继续发展严重的神经退行性病理学和神经炎症。有趣的是，没有检测到干扰素本身的基因表达上调。我们的数据表明，干扰素信号通路可能在神经元中c-Abl表达引起的病理过程中发挥作用，并且TCPP/tTA小鼠可能是研究无菌炎症和干扰素信号在脑中的作用的极好模型。
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. 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. 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. 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.
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DOI：
10.1523/jneurosci.0821-11.2011
发表时间：
2011-06-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Stevens SL;Leung PY;Vartanian KB;Gopalan B;Yang T;Simon RP;Stenzel-Poore MP
通讯作者：
Stenzel-Poore MP
影响因子：
2.6
作者：
Håkansson, P;Segal, D;Meltzer, PS
通讯作者：
Meltzer, PS
影响因子：
11
作者：
Conejero-Goldberg C;Hyde TM;Chen S;Dreses-Werringloer U;Herman MM;Kleinman JE;Davies P;Goldberg TE
通讯作者：
Goldberg TE
DOI：
10.3233/jad-2011-102025
发表时间：
2011
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Schlatterer SD;Tremblay MA;Acker CM;Davies P
通讯作者：
Davies P
影响因子：
14.9
作者：
Samarajiwa SA;Forster S;Auchettl K;Hertzog PJ
通讯作者：
Hertzog PJ