Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons
Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons
复制标题
DOI：
10.1073/pnas.95.7.4013
复制
发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Conneely, OM
中科院分区：
文献类型：
--
作者：
Saucedo-Cardenas, O;Quintana-Hau, JD;Conneely, OM
Nurr 1是转录因子核受体超家族的成员，其主要在中枢神经系统中表达，包括发育和成熟的多巴胺能神经元。最近的研究表明，Nurr 1对于腹侧中脑多巴胺能神经元的表型标记物的诱导是必需的，腹侧中脑多巴胺能神经元的产生由底板衍生的形态发生信号音刺猬（SHH）指定，但Nurr 1在这一分化途径中的确切作用尚未确定。为了进一步了解Nurr 1在最终分化途径中的作用，我们检测了Nurr 1无效突变小鼠中多巴胺细胞前体的命运。在这里，我们证明了Nurr 1在多巴胺细胞发育的后期起作用，以驱动腹侧中脑晚期多巴胺能前体神经元的分化。在Nurr 1缺失的情况下，产生多巴胺能神经元的神经上皮细胞在胚胎第11.5天采用正常的腹侧定位和神经元表型，其特征在于同源结构域转录因子和中脑标记物Ptx-3的表达，然而，这些晚期前体不能诱导多巴胺能表型，这表明Nurr 1对于指定中脑前体向完全多巴胺能表型的定型是必需的。此外，随着发育的进行，这些中脑多巴胺前体细胞在Nurr 1不存在的情况下退化，导致Ptx-3表达的丧失和伴随的新生无效突变小鼠中腹侧中脑神经元凋亡的增加，总之，这些数据表明，Nurr 1是必不可少的腹侧中脑晚期多巴胺能前体神经元的生存和最终分化成一个完整的多巴胺能表型。
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 new-born 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.