Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, and Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
J Mol Cell Biol. 2014 Feb;6(1):34-41. doi: 10.1093/jmcb/mjt046. Epub 2013 Dec 9.
Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain (VM), and controls and modulates the execution of motor, cognitive, affective, motivational, and rewarding behaviours. Degeneration of these neurons leads to motor deficits that are characteristic of Parkinson's disease, while their dysfunction is involved in the pathogenesis of psychiatric disorders including schizophrenia and addiction. Because the aetiology and therapeutic prospects for these diseases include neurodevelopmental aspects, substantial scientific interest has been focused on deciphering the mechanistic pathways that control the generation and survival of these neurons during embryonic development. Researches during the last decade revealed the pivotal role of the secreted Wnt1 ligand and its signalling cascade in the generation of the dopamine-synthesizing neurons in the mammalian VM. Here, we summarize the initial and more recent findings that have unravelled several Wnt1-controlled genetic networks required for the proliferation and commitment of VM progenitors to the dopaminergic cell fate during midgestational embryonic stages, and for the correct differentiation of these progenitors into postmitotic dopamine-synthesizing neurons at late midgestational embryonic and foetal stages.
合成神经递质多巴胺的神经元在哺乳动物大脑中发挥着至关重要的作用。合成多巴胺的神经元中最大、最重要的群体位于哺乳动物腹侧中脑（VM），控制和调节运动、认知、情感、动机和奖赏行为的执行。这些神经元的退化导致帕金森病的运动缺陷，而它们的功能障碍与包括精神分裂症和成瘾在内的精神疾病的发病机制有关。由于这些疾病的病因和治疗前景包括神经发育方面，因此科学界一直致力于解析控制这些神经元在胚胎发育过程中产生和存活的机制途径。过去十年的研究揭示了分泌性 Wnt1 配体及其信号级联在哺乳动物 VM 中产生合成多巴胺神经元的关键作用。在这里，我们总结了最初和最近的发现，这些发现揭示了几个 Wnt1 控制的遗传网络，这些网络对于 VM 祖细胞在中孕期胚胎阶段向多巴胺能细胞命运的增殖和定向以及对于这些祖细胞在中孕期晚期胚胎和胎儿阶段向有丝分裂后合成多巴胺神经元的正确分化是必需的。
