Restriction of neural precursor ability to respond to Nurr1 by early regional specification.
Restriction of neural precursor ability to respond to Nurr1 by early regional specification.
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DOI：
10.1371/journal.pone.0051798
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Augusti-Tocco G
中科院分区：
文献类型：
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作者：
Soldati C;Cacci E;Biagioni S;Carucci N;Lupo G;Perrone-Capano C;Saggio I;Augusti-Tocco G
在神经发育过程中，特定转录因子的空间调控表达对于中枢神经系统（CNS）区域化、神经前体（NP）的产生以及随后在限定区域内特定细胞类型的分化至关重要。转录因子Nurr1在中脑（MB）多巴胺能分化中起着关键作用。Nurr1控制参与多巴胺（DA）神经传递的关键基因的表达，例如酪氨酸羟化酶（TH）和DA转运蛋白（DAT），并促进胚胎干细胞中的多巴胺能表型。我们研究了来自小鼠中枢神经系统不同区域的细胞是否可以通过转录因子Nurr1的强制表达在体外定向分化为多巴胺能神经元。我们发现，Nurr1过表达可以促进多巴胺能细胞的命运规范，只有在NPs获得E13.5神经节隆起（GE）和MB，但不是在NPs分离E13.5皮质（CTX）和脊髓（SC）或成人脑室下区（SVZ）。与以前的研究一致，我们还表明Nurr1过表达可以增加小鼠胚胎干细胞中TH阳性神经元的产生。这些数据表明，Nurr1诱导多巴胺能表型的能力在CNS发育过程中受到限制，并且严重依赖于NPs衍生的区域。我们的研究结果表明，NPs的可塑性和他们的能力，激活多巴胺能分化程序响应Nurr1调节在神经发生的早期阶段，可能通过控制中枢神经系统区域化的机制。
During neural development, spatially regulated expression of specific transcription factors is crucial for central nervous system (CNS) regionalization, generation of neural precursors (NPs) and subsequent differentiation of specific cell types within defined regions. A critical role in dopaminergic differentiation in the midbrain (MB) has been assigned to the transcription factor Nurr1. Nurr1 controls the expression of key genes involved in dopamine (DA) neurotransmission, e.g. tyrosine hydroxylase (TH) and the DA transporter (DAT), and promotes the dopaminergic phenotype in embryonic stem cells. We investigated whether cells derived from different areas of the mouse CNS could be directed to differentiate into dopaminergic neurons in vitro by forced expression of the transcription factor Nurr1. We show that Nurr1 overexpression can promote dopaminergic cell fate specification only in NPs obtained from E13.5 ganglionic eminence (GE) and MB, but not in NPs isolated from E13.5 cortex (CTX) and spinal cord (SC) or from the adult subventricular zone (SVZ). Confirming previous studies, we also show that Nurr1 overexpression can increase the generation of TH-positive neurons in mouse embryonic stem cells. These data show that Nurr1 ability to induce a dopaminergic phenotype becomes restricted during CNS development and is critically dependent on the region of NPs derivation. Our results suggest that the plasticity of NPs and their ability to activate a dopaminergic differentiation program in response to Nurr1 is regulated during early stages of neurogenesis, possibly through mechanisms controlling CNS regionalization.
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