Ferri Anna L M, Lin Wei, Mavromatakis Yannis E, Wang Julie C, Sasaki Hiroshi, Whitsett Jeffrey A, Ang Siew-Lan
Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Development. 2007 Aug;134(15):2761-9. doi: 10.1242/dev.000141. Epub 2007 Jun 27.
The role of transcription factors in regulating the development of midbrain dopaminergic (mDA) neurons is intensively studied owing to the involvement of these neurons in diverse neurological disorders. Here we demonstrate novel roles for the forkhead/winged helix transcription factors Foxa1 and Foxa2 in the specification and differentiation of mDA neurons by analysing the phenotype of Foxa1 and Foxa2 single- and double-mutant mouse embryos. During specification, Foxa1 and Foxa2 regulate the extent of neurogenesis in mDA progenitors by positively regulating Ngn2 (Neurog2) expression. Subsequently, Foxa1 and Foxa2 regulate the expression of Nurr1 (Nr4a2) and engrailed 1 in immature neurons and the expression of aromatic l-amino acid decarboxylase and tyrosine hydroxylase in mature neurons during early and late differentiation of midbrain dopaminergic neurons. Interestingly, genetic evidence indicates that these functions require different gene dosages of Foxa1 and Foxa2. Altogether, our results demonstrate that Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.
由于中脑多巴胺能（mDA）神经元参与多种神经系统疾病，转录因子在调节其发育中的作用受到了深入研究。在此，我们通过分析Foxa1和Foxa2单突变和双突变小鼠胚胎的表型，证明了叉头/翼状螺旋转录因子Foxa1和Foxa2在mDA神经元的特化和分化中具有新的作用。在特化过程中，Foxa1和Foxa2通过正向调节Ngn2（Neurog2）的表达来调控mDA祖细胞中的神经发生程度。随后，在中脑多巴胺能神经元的早期和晚期分化过程中，Foxa1和Foxa2调节未成熟神经元中Nurr1（Nr4a2）和 engrailed 1的表达，以及成熟神经元中芳香族L-氨基酸脱羧酶和酪氨酸羟化酶的表达。有趣的是，遗传学证据表明这些功能需要不同剂量的Foxa1和Foxa2。总之，我们的结果表明，Foxa1和Foxa2以剂量依赖的方式调节中脑多巴胺能神经元发育的多个阶段。
