Li Aileen S W, Marikawa Yusuke
University of Hawaii John A. Burns School of Medicine, Institute for Biogenesis Research, Developmental and Reproductive Biology Graduate Program, Honolulu, HI 96813, USA.
University of Hawaii John A. Burns School of Medicine, Institute for Biogenesis Research, Developmental and Reproductive Biology Graduate Program, Honolulu, HI 96813, USA.
Reprod Toxicol. 2016 Dec;66:68-83. doi: 10.1016/j.reprotox.2016.09.015. Epub 2016 Sep 29.
Valproic acid (VPA), an antiepileptic drug, is a teratogen that causes neural tube and axial skeletal defects, although the mechanisms are not fully understood. We previously established a gastrulation model using mouse P19C5 stem cell embryoid bodies (EBs), which exhibits axial patterning and elongation morphogenesis in vitro. Here, we investigated the effects of VPA on the EB axial morphogenesis to gain insights into its teratogenic mechanisms. Axial elongation and patterning of EBs were inhibited by VPA at therapeutic concentrations. VPA elevated expression levels of various developmental regulators, including Cdx1 and Hoxa1, known transcriptional targets of retinoic acid (RA) signaling. Co-treatment of EBs with VPA and BMS493, an RA receptor antagonist, partially rescued axial elongation as well as gene expression profiles. These results suggest that VPA requires active RA signaling to interfere with EB morphogenesis.
丙戊酸（VPA）是一种抗癫痫药物，是一种致畸剂，可导致神经管和轴向骨骼缺陷，尽管其机制尚未完全明确。我们之前利用小鼠P19C5干细胞胚状体（EBs）建立了原肠胚形成模型，该模型在体外展现出轴向模式形成和伸长形态发生。在此，我们研究了VPA对EB轴向形态发生的影响，以深入了解其致畸机制。治疗浓度的VPA可抑制EB的轴向伸长和模式形成。VPA提高了各种发育调节因子的表达水平，包括Cdx1和Hoxa1，它们是已知的视黄酸（RA）信号转导的转录靶点。用VPA和RA受体拮抗剂BMS493共同处理EB，可部分挽救轴向伸长以及基因表达谱。这些结果表明，VPA需要活跃的RA信号来干扰EB形态发生。
