Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells
Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells
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DOI：
10.1016/j.ydbio.2004.07.038
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发表时间：
2004-11-01
影响因子：
2.7
通讯作者：
Okano, H
中科院分区：
文献类型：
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作者：
Okada, Y;Shimazaki, T;Okano, H
维甲酸(RA)是最重要的形态发生因子之一，其胚胎分布与中枢神经系统发育过程中的神经分化和定位有关。为了研究维甲酸对小鼠胚胎干细胞(ES细胞)神经分化的浓度依赖性影响，我们研究了不同浓度的维甲酸或BNIP拮抗剂Noggin对聚集成类胚体(EBS)的ES细胞神经和区域特异性基因的精确表达谱。RA以浓度依赖的方式促进神经分化和尾化，并发现RA的浓度调节背腹的同一性，即较高浓度的RA诱导背侧表型，较低浓度的RA诱导更多的腹侧表型。Sonic hedgehog Protein(Shh-N)N-末端的高表达是由于低浓度RA处理后，Shh-N的N端表达水平升高，因为Shh信号的抑制剂环丙胺可以抑制Shh-N的表达。这些发现表明，在小鼠ES细胞分化过程中，RA浓度严格且同时调节神经化和位置规范，并有可能用它来建立一种控制ES细胞来源的神经细胞的策略。(C)2004 Elsevier Inc.保留所有权利。
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 BNIP antagonist Noggin. RA promoted both neural differentiation and caudalization in a concentration-dependent manner, and the concentration of RA was found to regulate dorsoventral 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. (C) 2004 Elsevier Inc. All rights reserved.