Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9131-6. doi: 10.1073/pnas.1016679108. Epub 2011 May 16.
Understanding the control of cell-fate choices during embryonic stem cell (ESC) differentiation is crucial for harnessing strategies for efficient production of desired cell types for pharmaceutical drug screening and cell transplantation. Here we report the identification of the zinc finger-like doublesex and mab-3-related transcription factor 5 (Dmrt5) as a marker for mammalian ventral-medial mesencephalic neuroepithelium that give rise to dopamine neurons. Gain- and loss-of-function studies in ESC demonstrate that Dmrt5 is critically involved in the specification of ventral-medial neural progenitor cell fate and the subsequent generation of dopamine neurons expressing essential midbrain characteristics. Genome-wide analysis of Dmrt5-mediated transcriptome changes and expression profiling of ventral-medial and ventral-lateral mesencephalic neuroepithelium revealed suppressive and inductive regulatory roles for Dmrt5 in the transcription program associated with the ventral-medial neural progenitor fates. Together, these data identify Dmrt5 as an important player in ventral mesencephalic neural fate specification.
理解胚胎干细胞 (ESC) 分化过程中细胞命运选择的控制对于利用有效产生所需细胞类型的策略至关重要，这些细胞类型可用于药物筛选和细胞移植。在这里，我们报告了锌指样双性和 mab-3 相关转录因子 5 (Dmrt5) 的鉴定，它是产生多巴胺神经元的哺乳动物腹侧-内侧中脑神经上皮的标志物。ESC 的获得和丧失功能研究表明，Dmrt5 对于腹侧-内侧神经祖细胞命运的特化以及随后产生表达中脑重要特征的多巴胺神经元至关重要。对 Dmrt5 介导的转录组变化的全基因组分析和腹侧-内侧和腹侧-外侧中脑神经上皮的表达谱分析揭示了 Dmrt5 在与腹侧-内侧神经祖细胞命运相关的转录程序中具有抑制和诱导调节作用。总之，这些数据表明 Dmrt5 是腹侧中脑神经命运特化的重要参与者。
