Okada Yohei, Shimazaki Takuya, Sobue Gen, Okano Hideyuki
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Dev Biol. 2004 Nov 1;275(1):124-42. doi: 10.1016/j.ydbio.2004.07.038.
Retinoic acid (RA) is one of the most important morphogens, and its embryonic distribution correlates with neural differentiation and positional specification in the developing central nervous system. To investigate the concentration-dependent effects of RA on neural differentiation of mouse embryonic stem cells (ES cells), we investigated the precise expression profiles of neural and regional specific genes by ES cells aggregated into embryoid bodies (EBs) exposed to various concentrations of RA or the BMP antagonist Noggin. RA promoted both neural differentiation and caudalization in a concentration-dependent manner, and the concentration of RA was found to regulate dorso-ventral identity, i.e., higher concentrations of RA induced a dorsal phenotype, and lower concentrations of RA induced a more ventral phenotype. The induction of the more ventral phenotype was due to the higher expression level of the N-terminus of sonic hedgehog protein (Shh-N) when treated with low concentration RA, as it was abrogated by an inhibitor of Shh signaling, cyclopamine. These findings suggest that the concentration of RA strictly and simultaneously regulates the neuralization and positional specification during differentiation of mouse ES cells and that it may be possible to use it to establish a strategy for controlling the identity of ES-cell-derived neural cells.
视黄酸(RA)是最重要的形态发生素之一,其在胚胎中的分布与发育中的中枢神经系统的神经分化和位置特化相关。为了研究RA对小鼠胚胎干细胞(ES细胞)神经分化的浓度依赖性影响,我们通过将ES细胞聚集成胚状体(EBs),并使其暴露于不同浓度的RA或骨形态发生蛋白拮抗剂Noggin,来研究神经和区域特异性基因的精确表达谱。RA以浓度依赖性方式促进神经分化和尾化,并且发现RA的浓度调节背腹身份,即较高浓度的RA诱导背侧表型,而较低浓度的RA诱导更腹侧的表型。当用低浓度RA处理时,更腹侧表型的诱导是由于音猬因子蛋白(Shh-N)N端的表达水平较高,因为它被Shh信号通路的抑制剂环杷明所消除。这些发现表明,RA的浓度在小鼠ES细胞分化过程中严格且同时调节神经化和位置特化,并且有可能利用它来建立一种控制ES细胞来源的神经细胞身份的策略。