Identification of early-responsive genes correlated to valproic acid-induced neural tube defects in mice
Identification of early-responsive genes correlated to valproic acid-induced neural tube defects in mice
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DOI：
10.1002/bdra.20131
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发表时间：
2005-04-01
影响因子：
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通讯作者：
Fujiwara, M
中科院分区：
文献类型：
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作者：
Okada, A;Kushima, K;Fujiwara, M
背景：丙戊酸（VPA）会导致新生小鼠神经管闭合失败。然而，其致畸的分子机制尚不清楚。本研究旨在调查 VPA 破坏对小鼠正常神经管发育的全基因组影响。方法：对在妊娠第 8 天用 VPA 处理 1 小时的 NMRI 小鼠胚胎的头部进行微阵列分析。随后，我们在实时 PCR 研究中尝试通过使用降低致畸作用的 VPA 类似物丙戊酰胺 (VPD) 和丙诺酰胺 (VCD) 来分离与 VPA 致畸作用相关的变化基因。结果：微阵列结果表明，在神经形成过程中，许多基因（其中一些功能已知，一些功能未知）在注射 VPA 后增加或减少。一些基因以与 VPA 相同的方式受到 VPD 或 VCD 的影响，但其他基因则不会受到类似物的改变。通过这种方式，我们的系统识别出了 11 个增加的基因和 20 个减少的基因。注释分析显示，增加的基因包括gadd45b、ier5、pert、phfl3、pou3f1和sox4，减少的基因包括ccne2、ecnl、gas5、egr2、sirt1和zfp105。结论：这些发现表明，在神经管细胞的细胞周期和凋亡途径中起作用的基因的表达变化强烈预期与 VPA 的致畸活性有关，但与抗癫痫活性无关。我们的方法使得发育中的神经管中受 VPA 直接影响的分子目录得以扩展。出生缺陷研究（A 部分）73:229-238，(c) 2005。2005 Wiley-Liss, Inc.
BACKGROUND: Valproic acid (VPA) causes the failure of neural tube closure in newborn mice. However, the molecular mechanism of its teratogenesis is unknown. This study was conducted to investigate the genomewide effects of VPA disruption of normal neural tube development in mice. METHODS: Microarray analysis was performed on the head part of NMRI mouse embryos treated for 1 hr with VPA on gestational day (GD) 8. Subsequently, we attempted to isolate genes that changed in correlation with the teratogenic action of VPA by employing reduced teratogenic VPA analogs, valpromide (VPD) and valnoctamide (VCD), in a real-time PCR study. RESULTS: Microarray results demonstrated that during neurulation, many genes, some of whose functions are known and some unknown, were either increased or decreased after VPA injection. Some genes were affected by VPD or VCD in the same way as VPA, but others were not changed by the analogs. In this way, our system identified 11 increased and 20 decreased genes. Annotation analysis revealed that the increased genes included gadd45b, ier5, pert, phfl3, pou3f1, and sox4, and the decreased genes included ccne2, ecnl, gas5, egr2, sirt1, and zfp105. CONCLUSIONS: These findings demonstrate that expression changes in genes having roles inn the cell cycle and apoptosis pathways of neural tube cells were strongly expected to relate to the teratogenic, but not antiepileptic, activity of VPA. Our approach has allowed the expansion of the catalog of molecules immediately affected by VPA in the developing neural tube. Birth Defects Research (Part A) 73:229-238, (c) 2005. 2005 Wiley-Liss, Inc.