The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons
The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons
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DOI：
10.1016/j.mcn.2004.09.008
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Kim, KS
中科院分区：
文献类型：
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作者：
Chung, S;Hedlund, E;Kim, KS
在帕金森病（PD）中，A9多巴胺能（DA）神经元群是最脆弱的。我们对小鼠胚胎干细胞（ES）进行基因工程改造，使其表达转录因子Nurr1或Pitx3。体外分化表达pitx3的ES细胞后，表达醛脱氢酶2 （AHD2）的DA神经元比例增加，但DA神经元总数不变。在背纹状体的A9 DA神经元中，AHD2的表达水平最高。此外，对体外分化的表达pitx3的ES细胞进行实时PCR分析，发现A9 DA神经元中高表达的基因上调。当移植到小鼠纹状体时，表达pra的细胞产生的表达ahd2的DA神经元比例增加。相比之下，在表达nurr1的ES细胞中，所有中脑DA标记物均增加，导致体外和体内DA神经元总数增加，而表达ahd2的DA神经元比例没有变化。我们使用ES细胞的功能获得分析的数据表明，Pitx3可能对a9样神经元特性的规范和/或维持很重要，而Nurr1影响整个中脑DA规范。这些发现可能对修饰胚胎干细胞以产生用于PD移植治疗的最佳细胞来源具有重要意义。(C) 2004爱思唯尔公司版权所有。
The A9 dopaminergic (DA) neuronal group projecting to the dorsal striatum is the most vulnerable in Parkinson's disease (PD). We genetically engineered mouse embryonic stem (ES) cells to express the transcription factors Nurr1 or Pitx3. After in vitro differentiation of Pitx3-expressing ES cells, the proportion of DA neurons expressing aldehyde dehydrogenase 2 (AHD2) increased, while the total number of DA neurons remained the same. The highest levels of AHD2 expression were observed in mouse A9 DA neurons projecting to the dorsal striatum. Furthermore, real-time PCR analyses of in vitro differentiated Pitx3-expressing ES cells revealed that genes highly expressed in A9 DA neurons were up-regulated. When transplanted into the mouse striatum, PRA-expressing cells generated an increased proportion of AHD2-expressing DA neurons. Contrastingly, in Nurr1-expressing ES cells, increases of all midbrain DA markers were observed, resulting in a higher total number of DA neurons in vitro and in vivo, whereas the proportion of AHD2-expressing DA neurons was not changed. Our data, using gain-of-function analysis of ES cells, suggest that Pitx3 may be important for specification and/or maintenance of A9-like neuronal properties, while Nurr1 influences overall midbrain DA specification. These findings may be important for modifying ES cells to generate an optimal cell source for transplantation therapy of PD. (C) 2004 Elsevier Inc. All rights reserved.