Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system, including developing and mature dopaminergic neurons. Recent studies have demonstrated that Nurr1 is essential for the induction of phenotypic markers of ventral mid-brain dopaminergic neurons whose generation is specified by the floor plate-derived morphogenic signal sonic hedgehog (SHH), but the precise role of Nurr1 in this differentiative pathway has not been established. To provide further insights into the role of Nurr1 in the final differentiation pathway, we have examined the fate of dopamine cell precursors in Nurr1 null mutant mice. Here we demonstrate that Nurr1 functions at the later stages of dopamine cell development to drive differentiation of ventral mesencephalic late dopaminergic precursor neurons. In the absence of Nurr1, neuroepithelial cells that give rise to dopaminergic neurons adopt a normal ventral localization and neuronal phenotype characterized by expression of the homeodomain transcription factor and mesencephalic marker, Ptx-3, at embryonic day 11.5. However, these late precursors fail to induce a dopaminergic phenotype, indicating that Nurr1 is essential for specifying commitment of mesencephalic precursors to the full dopaminergic phenotype. Further, as development progresses, these mid-brain dopamine precursor cells degenerate in the absence of Nurr1, resulting in loss of Ptx-3 expression and a concomitant increase in apoptosis of ventral midbrain neurons in newborn null mutant mice. Taken together, these data indicate that Nurr1 is essential for both survival and final differentiation of ventral mesencephalic late dopaminergic precursor neurons into a complete dopaminergic phenotype.

Nurr1是核受体超家族转录因子的一员，主要表达于中枢神经系统（central nervous system），涵盖发育中和成熟的多巴胺能神经元（dopaminergic neurons）。近期研究表明，Nurr1对于诱导腹侧中脑多巴胺能神经元的表型标志物至关重要——这类神经元的生成由底板源性形态发生信号音猬因子（sonic hedgehog, SHH）所调控，但Nurr1在该分化通路中的具体作用尚未阐明。为进一步揭示Nurr1在终末分化通路中的功能，我们对Nurr1基因敲除小鼠（Nurr1 null mutant mice）中的多巴胺能细胞前体命运进行了检测。本研究证实，Nurr1在多巴胺能细胞发育的晚期阶段发挥功能，驱动腹侧中脑晚期多巴胺能前体神经元的分化。在Nurr1缺失的情况下，产生多巴胺能神经元的神经上皮细胞可正常定位于腹侧区域，并呈现出以同源结构域转录因子（homeodomain transcription factor）和中脑标志物Ptx-3的表达为特征的神经元表型，该特征在胚胎第11.5天（embryonic day 11.5）即可观察到。然而，这些晚期前体细胞无法诱导出多巴胺能表型，这表明Nurr1是中脑前体细胞定向分化为完整多巴胺能表型的必需因子。进一步研究发现，随着发育进程推进，在缺失Nurr1的条件下，上述中脑多巴胺能前体细胞会发生退化，导致Ptx-3表达丧失，并伴随新生Nurr1基因敲除小鼠腹侧中脑神经元的细胞凋亡（apoptosis）水平升高。综上，本研究数据表明，Nurr1对于腹侧中脑晚期多巴胺能前体神经元的存活，以及其终末分化为完整多巴胺能表型均不可或缺。