Pitx3 Is a Critical Mediator of GDNF-Induced BDNF Expression in Nigrostriatal Dopaminergic Neurons
Pitx3 Is a Critical Mediator of GDNF-Induced BDNF Expression in Nigrostriatal Dopaminergic Neurons
复制标题
Pitx3 是黑质纹状体多巴胺能神经元 GDNF 诱导 BDNF 表达的关键介质
DOI：
10.1523/jneurosci.0898-11.2011
复制
发表时间：
2011-09-07
影响因子：
5.3
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Peng, Changgeng;Aron, Liviu;Le, Weidong
Pitx 3是哺乳动物中脑多巴胺能神经元正常发育和存活的关键同源域转录因子。该基因的几种变体与人类帕金森病（PD）有关，小鼠中缺乏Pitx 3会导致PD中受影响最大的黑质黑质（SNc）mdDA神经元的优先损失。目前尚不清楚Pitx 3活性如何促进SNc mdDA神经元的存活，以及在这种情况下哪些因子作用于Pitx 3的上游和下游。在这里，我们发现胶质细胞源性神经营养因子（GDNF）在小鼠腹侧中脑（VM）的瞬时表达通过NF-κ B介导的信号转导诱导Pitx 3的转录，而Pitx 3反过来又需要激活脑源性神经营养因子（BDNF）在吻外侧（SNc）mdDA神经元亚群在胚胎发育过程中的表达。在Pitx 3 −/−小鼠中，BDNF表达的缺失与mdDA神经元亚群的凋亡细胞死亡增加相关，而用BDNF处理VM细胞培养物可增加Pitx 3 −/− mdDA神经元的存活。最重要的是，只有BDNF，而不是GDNF保护mdDA神经元免受6-羟基多巴胺诱导的细胞死亡的Pitx 3的情况下。由于GDNF，Pitx 3和BDNF表达的前馈调节在成年啮齿动物大脑中也持续存在，我们的数据表明，这三个因素之间的调节相互作用的破坏导致Pitx 3 −/−突变小鼠以及人类PD中mdDA神经元的丢失。
Pitx3 is a critical homeodomain transcription factor for the proper development and survival of mesodiencephalic dopaminergic (mdDA) neurons in mammals. Several variants of this gene have been associated with human Parkinson's disease (PD), and lack of Pitx3 in mice causes the preferential loss of substantia nigra pars compacta (SNc) mdDA neurons that are most affected in PD. It is currently unclear how Pitx3 activity promotes the survival of SNc mdDA neurons and which factors act upstream and downstream of Pitx3 in this context. Here we show that a transient expression of glial cell line-derived neurotrophic factor (GDNF) in the murine ventral midbrain (VM) induces transcription of Pitx3 via NF-κB-mediated signaling, and that Pitx3 is in turn required for activating the expression of brain-derived neurotrophic factor (BDNF) in a rostrolateral (SNc) mdDA neuron subpopulation during embryogenesis. The loss of BDNF expression correlates with the increased apoptotic cell death of this mdDA neuronal subpopulation in Pitx3−/− mice, whereas treatment of VM cell cultures with BDNF augments the survival of the Pitx3−/− mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3−/− mutant mice and perhaps also in human PD.