Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars
Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars
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DOI：
10.1073/pnas.0903066106
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发表时间：
2009-07-14
影响因子：
11.1
通讯作者：
Subburaju, Sivan
中科院分区：
文献类型：
--
作者：
Benes, Francine M.;Lim, Benjamin;Subburaju, Sivan
精神分裂症 (SZ) 和双相情感障碍 (BD) 中的 GABA 细胞功能障碍均涉及 GAD(67) 表达减少，尽管这种变化涉及两种疾病中根本不同的基因网络。这两个网络共有的一个基因是细胞周期蛋白 D2，它是细胞周期调节的关键组成部分，在 SZ 中表达增加，但在 BD 中表达减少。由于细胞周期调控在维持功能分化和DNA修复中的重要性，目前的研究检查了G(1)和G(2)检查点所涉及的基因，以产生关于SZ和BD海马GABA细胞表型调控的新假设。结果表明，SZ 和 BD 的细胞周期调控发生了显着变化，这些变化包括控制 E2F/DP-1 靶基因表达的转录复合物 (TC)，这对进展到 G(2)/M 至关重要。对 DNA 修复至关重要的甲基 CpG 结合域蛋白 (MBD4) 在 SZ 和 BD 的 CA3/2 和 CA1 的方向层 (SO) 中显着上调。然而，与 TC 以及 G(1) 和 G(2) 检查点相关的其他基因在 SZ 和 BDS 的 CA3/2 和 CA1 的 SO 中显示出复杂的表达变化。总体而言，观察到的表达模式表明，海马 GABA 细胞的功能分化和/或基因组完整性的调节根据诊断及其在三突触通路中的位置而变化。
GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD(67) expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G(1) and G(2) checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G(2)/M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G(1) and G(2) checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.