Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype
Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype
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DOI：
10.1073/pnas.0511153103
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发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Abeliovich, A
中科院分区：
文献类型：
--
作者：
Martinat, C;Bacci, JJ;Abeliovich, A
中脑多巴胺I神经元在随意运动的调节中起着核心作用，它们的变性与帕金森病有关。细胞替代疗法，特别是胚胎干（ES）细胞衍生的DA神经元，为帕金森病提供了一个潜在的治疗场所。我们试图鉴定能够增强ES细胞培养物成熟为中脑DA神经元表型的基因。通过表达分析和功能缺失敲除小鼠研究，许多转录因子与中脑DA神经元的发育有关，包括Nurr 1、Pitx 3、Lmx 1b、Engrailed-1和Engrailed-2。然而，这些因素似乎都不足以单独诱导成熟的中脑DA神经元表型在体外ES细胞培养，这表明一个更复杂的调控网络。在这里，我们表明，Nurr 1和Pitx 3合作促进终端成熟的中脑DA神经元表型在小鼠和人类ES细胞培养。
Midbrain dopamine I neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson's disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson's disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro, suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures.