Queensland Centre for Mental Health Research, Wacol, QLD 4076, Australia.
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
Int J Mol Sci. 2021 Jul 6;22(14):7268. doi: 10.3390/ijms22147268.
The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 () is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.
多巴胺能（DA）系统对一系列大脑功能很重要，并且皮质下 DA 的发育先于许多皮质成熟过程。DA 系统的功能障碍与神经精神疾病有关，如精神分裂症、抑郁症和成瘾。DA 神经元细胞命运由决定 DA 神经元特化、分化和成熟的复杂转录因子网络控制。越来越多的证据表明，这些转录因子受新发现的非编码 RNA 的调节。然而，关于 DA 神经元发育，非编码 RNA 的作用知之甚少。长链非编码 RNA（lncRNA）HOX-反义基因间 RNA 髓系 1（）存在于成年 DA 神经元中，表明它可能在 DA 系统中具有调节作用。此外，在人类干细胞中的神经元分化中涉及，表明它也可能在早期 DA 神经元发育中发挥作用。为了确定其在早期 DA 神经元发育中的作用，我们使用 RNAi 在体外的人类神经母细胞瘤细胞系中以及使用新型在体电穿孔技术在体内的小鼠 DA 祖细胞中敲低。抑制降低了一系列关键的 DA 神经元特化因子的表达，并损害了 DA 神经元的分化和成熟。这些结果提供了证据表明在 DA 神经元发育和分化中具有功能性作用。对 lncRNA 在 DA 系统发育中的作用的理解可能对大脑发育和神经发育障碍（如精神分裂症）具有更广泛的意义。
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