Reprogramming of genetic networks during initiation of the fetal alcohol syndrome
Reprogramming of genetic networks during initiation of the fetal alcohol syndrome
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DOI：
10.1002/dvdy.21048
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发表时间：
2007-02-01
影响因子：
2.5
通讯作者：
Knudsen, Thomas B.
中科院分区：
文献类型：
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作者：
Green, Maia L.;Singh, Amar V.;Knudsen, Thomas B.
胎儿酒精谱系障碍 (FASD) 是由于母亲饮酒导致的先天缺陷。我们使用非先验方法来优先考虑早期小鼠胚胎酒精诱导致畸过程中的候选途径。两个 C57BL/6 亚株（B6J、B6N）作为研究的基础。给怀孕母鼠注射酒精（第 8 天 2 x 2.9 g/kg 乙醇，间隔 4 小时）诱导 B6J 胚胎中 FASD 的发生率高于 B6N 胚胎。反暴露于 PK11195 (4 mg/kg) 显着保护 B6J 胚胎，但轻微促进 B6N 胚胎中的 FASD。第一次母体酒精注射后 3 小时，对胚胎头褶进行微阵列转录谱分析（GEO 数据系列登录号 GSE1074）。该分析揭示了亚株特异性和/或 PK11195 依赖性的代谢和细胞重编程。绘制乙醇反应性 KEGG（京都基因和基因组百科全书）途径揭示了 B6N 胚胎中核糖体蛋白和蛋白酶体的下调以及糖酵解和磷酸戊糖途径的上调；两个亚株中的紧密连接、粘着斑、粘附连接以及肌动蛋白细胞骨架的调节（以及 Wnt 信号传导和细胞凋亡的近乎显着的上调）途径均显着上调。根据这些改变的基因通过计算构建的表达网络确定了 EtOH 在几个中心（MAPK1、ALDH3A2、CD14、PFKM、TNFRSF1A、RPS6、IGF1、EGFR、PTEN）的入口点和 PK11195 在 AKT1 的入口点。我们的研究结果与越来越多的观点一致，即发育过程中接触酒精会改变将受体激活与细胞骨架重组联系起来的常见信号通路。细胞运动和代谢能力的程序性转变进一步意味着细胞信号和反应由线粒体识别位点 PK11195 整合。发育动力学 236.613-631, 2007。(c) 2007 Wiley-Liss, Inc.
Fetal Alcohol Spectrum Disorders (FASD) are birth defects that result from maternal alcohol use. We used a non a priori approach to prioritize candidate pathways during alcohol-induced teratogenicity in early mouse embryos. Two C57BL/6 substrains (B6J, B6N) served as the basis for study. Dosing pregnant dams with alcohol (2 x 2.9 g/kg ethanol spaced 4 hr on day 8) induced FASD in B6J at a higher incidence than B6N embryos. Counter-exposure to PK11195 (4 mg/kg) significantly protected B6J embryos but slightly promoted FASD in B6N embryos. Microarray transcript profiling was performed on the embryonic headfold 3 hr after the first maternal alcohol injection (GEO data series accession GSE1074). This analysis revealed metabolic and cellular reprogramming that was substrain-specific and/or PK11195-dependent. Mapping ethanolresponsive KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed down-regulation of ribosomal proteins and proteasome, and up-regulation of glycolysis and pentose phosphate pathway in B6N embryos; and significant up-regulation of tight junction, focal adhesion, adherens junction, and regulation of the actin cytoskeleton (and near-significant up-regulation of Wnt signaling and apoptosis) pathways in both substrains. Expression networks constructed computationally from these altered genes identified entry points for EtOH at several hubs (MAPK1, ALDH3A2, CD14, PFKM, TNFRSF1A, RPS6, IGF1, EGFR, PTEN) and for PK11195 at AKT1. Our findings are consistent with the growing view that developmental exposure to alcohol alters common signaling pathways linking receptor activation to cytoskeletal reorganization. The programmatic shift in cell motility and metabolic capacity further implies cell signals and responses that are integrated by the mitochondrial recognition site for PK11195. Developmental Dynamics 236.613-631, 2007. (c) 2007 Wiley-Liss, Inc.