Simon Horst H, Bhatt Lavinia, Gherbassi Daniel, Sgadó Paola, Alberí Lavinia
Center for Neuroscience, Department of Neuroanatomy, University of Heidelberg, 69120 Heidelberg, Germany.
Ann N Y Acad Sci. 2003 Jun;991:36-47.
Midbrain dopaminergic neurons are the main source of dopamine in the mammalian central nervous system and are associated with one of the most prominent human neurological disorders, Parkinson's disease. During development, they are induced in the ventral midbrain by an interaction between two diffusible factors, SHH and FGF8. The local identity of this part of the midbrain is probably determined by the combinatorial expression of three transcription factors, Otx2, Pax2, and Pax5. After the last cell division, the neurons start to express transcription factors that control further differentiation and the manifestation of cellular properties characteristic for adult dopaminergic neurons of the substantia nigra compacta and the ventral tegmentum. The first to appear is the LIM-homeodomain transcription factor, Lmx1b. It is essential for the survival of these neurons, and it regulates the expression of another transcription factor, Pitx3, an activator of tyrosine hydroxylase. Lmx1b is followed by the orphan steroid receptor Nurr1. It is essential for the expression of the dopaminergic phenotype. Several genes involved in dopamine synthesis, transport, release, and reuptake are regulated by Nurr1. This requirement is specific to the midbrain dopaminergic neurons, since other populations of the same neurotransmitter phenotype develop normally in absence of the gene. A day after Nurr1, two homeodomain transcription factors, engrailed-1 and -2, are expressed. In animals deficient in the two genes, the midbrain dopaminergic neurons are generated, but then fail to differentiate and disappear very rapidly. Interestingly, alpha-synuclein, a gene recently linked to familial forms of Parkinson's disease, is regulated by engrailed-1 and -2.
中脑多巴胺能神经元是哺乳动物中枢神经系统中多巴胺的主要来源，与最突出的人类神经疾病之一帕金森病相关。在发育过程中，它们由两种可扩散因子SHH和FGF8之间的相互作用诱导产生于腹侧中脑。中脑这一部分的局部特征可能由三种转录因子Otx2、Pax2和Pax5的组合表达所决定。在最后一次细胞分裂后，神经元开始表达控制进一步分化以及黑质致密部和腹侧被盖区成年多巴胺能神经元细胞特性表现的转录因子。最先出现的是LIM同源结构域转录因子Lmx1b。它对这些神经元的存活至关重要，并调节另一种转录因子Pitx3的表达，Pitx3是酪氨酸羟化酶的激活剂。Lmx1b之后是孤儿类固醇受体Nurr1。它对多巴胺能表型的表达至关重要。几种参与多巴胺合成、转运、释放和再摄取的基因受Nurr1调控。这种需求是中脑多巴胺能神经元所特有的，因为相同神经递质表型的其他群体在该基因缺失的情况下仍能正常发育。在Nurr1出现一天后，两种同源结构域转录因子engrailed-1和-2开始表达。在这两种基因缺陷的动物中，中脑多巴胺能神经元能够产生，但随后无法分化并很快消失。有趣的是，α-突触核蛋白，一种最近与帕金森病家族形式相关的基因，受engrailed-1和-2调控。
