Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht , 3584 CG Utrecht , The Netherlands.
Biol Open. 2012 Aug 15;1(8):693-704. doi: 10.1242/bio.20121230. Epub 2012 May 17.
Meso-diencephalic dopaminergic (mdDA) neurons are critical for motor control and cognitive functioning and their loss or dysfunction is associated with disorders such as Parkinson's disease (PD), schizophrenia and addiction. However, relatively little is known about the molecular mechanisms underlying mdDA neuron development and maintenance. Here, we determined the spatiotemporal map of genes involved in the development of mdDA neurons to gain further insight into their molecular programming. Genome-wide gene expression profiles of the developing ventral mesencephalon (VM) were compared at different developmental stages leading to the identification of novel regulatory roles of neuronal signaling through nicotinic acthylcholine receptors (Chrna6 and Chrnb3 subunits) and the identification of novel transcription factors (Oc2 and 3) involved in the generation of the mdDA neuronal field. We show here that Pitx3, in cooperation with Nurr1, is the critical component in the activation of the Chrna6 and Chrnb3 subunits in mdDA neurons. Furthermore, we provide evidence of two divergent regulatory pathways resulting in the expression of Chrna6 and Chrnb3 respectively.
中脑多巴胺能（mdDA）神经元对运动控制和认知功能至关重要，其损失或功能障碍与帕金森病（PD）、精神分裂症和成瘾等疾病有关。然而，关于 mdDA 神经元发育和维持的分子机制，我们知之甚少。在这里，我们确定了参与 mdDA 神经元发育的基因的时空图谱，以更深入地了解它们的分子编程。通过比较不同发育阶段的腹侧中脑（VM）的全基因组基因表达谱，我们确定了神经元信号通过烟碱型乙酰胆碱受体（Chrna6 和 Chrnb3 亚基）的新的调节作用，以及涉及 mdDA 神经元场生成的新的转录因子（Oc2 和 3）的新的调节作用。我们在这里表明，Pitx3 与 Nurr1 合作，是 mdDA 神经元中 Chrna6 和 Chrnb3 亚基激活的关键组成部分。此外，我们提供了证据表明，两个不同的调节途径分别导致 Chrna6 和 Chrnb3 的表达。
