Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells
Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells
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DOI：
10.1074/jbc.m107013200
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发表时间：
2001-11-16
影响因子：
4.8
通讯作者：
Perlmann, T
中科院分区：
文献类型：
--
作者：
Castro, DS;Hermanson, E;Perlmann, T
多巴胺细胞在胚胎发育期间在中脑腹侧产生。这些细胞在帕金森病患者中的进行性变性，以及通过移植体外产生的多巴胺细胞的潜在治疗益处，引发了人们对理解这些细胞发育过程的强烈兴趣。Nurr 1是中脑多巴胺能神经元发育所必需的孤儿核受体。然而，Nurr 1促进多巴胺细胞分化的机制仍然未知。在这项研究中，我们使用了多巴胺合成细胞系（MN 9D）与未成熟的特点，以分析Nurr 1在多巴胺细胞发育的功能。结果表明，Nurr 1可以诱导这些细胞的细胞周期停滞和高度分化的细胞形态。这两种功能都是通过DNA结合依赖性机制介导的，不需要Nurr 1与异源二聚化伴侣类维生素A X受体相互作用。然而，维甲酸可以促进MN 9D细胞的分化独立于Nurr 1。重要的是，密切相关的孤儿受体NGFI-B和Nor 1也能够诱导细胞周期停滞和分化。因此，NGFI-B/Nurr 1/Nor 1孤儿受体的生长抑制活性，沿着它们在发育期间和在成人中的广泛表达模式，提示在发育胚胎和成人组织中控制细胞增殖的更普遍的作用。
Dopamine cells are generated in the ventral midbrain during embryonic development. The progressive degeneration of these cells in patients with Parkinson's disease, and the potential therapeutic benefit by transplantation of in vitro generated dopamine cells, has triggered intense interest in understanding the process whereby these cells develop. Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. However, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study we have used a dopamine-synthesizing cell line (MN9D) with immature characteristics to analyze the function of Nurr1 in dopamine cell development. The results demonstrate that Nurr1 can induce cell cycle arrest and a highly differentiated cell morphology in these cells. These two functions were both mediated through a DNA binding-dependent mechanism that did not require Nurr1 interaction with the heterodimerization partner retinoid X receptor. However, retinoids can promote the differentiation of MN9D cells independently of Nurr1. Importantly, the closely related orphan receptors NGFI-B and Nor1 were also able to induce cell cycle arrest and differentiation. Thus, the growth inhibitory activities of the NGFI-B/Nurr1/ Nor1 orphan receptors, along with their widespread expression patterns both during development and in the adult, suggest a more general role in control of cell proliferation in the developing embryo and in adult tissues.