Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Stem Cells Dev. 2020 Sep 1;29(17):1145-1159. doi: 10.1089/scd.2020.0046. Epub 2020 Jun 17.
Bipolar disorder (BP) is a complex psychiatric condition characterized by severe fluctuations in mood for which underlying pathological mechanisms remain unclear. Family and twin studies have identified a hereditary component to the disorder, but a single causative gene (or set of genes) has not been identified. MicroRNAs (miRNAs) are small, noncoding RNAs ∼20 nucleotides in length, that are responsible for the posttranslational regulation of multiple genes. They have been shown to play important roles in neural development as well as in the adult brain, and several miRNAs have been reported to be dysregulated in postmortem brain tissue isolated from bipolar patients. Because there are no viable cellular models to study BP, we have taken advantage of the recent discovery that somatic cells can be reprogrammed to pluripotency then directed to form the full complement of neural cells. Analysis of RNAs extracted from Control and BP patient-derived neurons identified 58 miRNAs that were differentially expressed between the two groups. Using quantitative polymerase chain reaction we validated six miRNAs that were elevated and two miRNAs that were expressed at lower levels in BP-derived neurons. Analysis of the targets of the miRNAs indicate that they may regulate a number of cellular pathways, including axon guidance, Mapk, Ras, Hippo, Neurotrophin, and Wnt signaling. Many are involved in processes previously implicated in BP, such as cell migration, axon guidance, dendrite and synapse development, and function. We have validated targets of several different miRNAs, including , , , and as direct targets of differentially expressed miRNAs using luciferase assays. Identification of pathways altered in patient-derived neurons suggests that disruption of these regulatory networks that may contribute to the complex phenotypes in BP.
双相情感障碍(BP)是一种复杂的精神疾病,其特征是情绪严重波动,其潜在的病理机制尚不清楚。家族和双胞胎研究已经确定了该疾病的遗传成分,但尚未确定单个致病基因(或一组基因)。微小 RNA(miRNA)是长度约为 20 个核苷酸的小非编码 RNA,负责多个基因的翻译后调控。它们已被证明在神经发育以及成年大脑中发挥重要作用,并且已经报道了几种 miRNA 在从双相情感障碍患者分离的死后脑组织中失调。由于没有可行的细胞模型来研究 BP,我们已经利用最近的发现,即体细胞可以被重编程为多能性,然后指导它们形成完整的神经细胞。从对照和 BP 患者来源的神经元中提取的 RNA 的分析确定了 58 个 miRNA 在两组之间表达不同。使用定量聚合酶链反应,我们验证了在 BP 衍生神经元中升高的六个 miRNA 和两个表达水平较低的 miRNA。对 miRNA 的靶标分析表明,它们可能调节许多细胞途径,包括轴突导向、Mapk、Ras、Hippo、神经营养因子和 Wnt 信号传导。许多参与了先前与 BP 相关的过程,如细胞迁移、轴突导向、树突和突触发育以及功能。我们已经使用荧光素酶测定验证了几种不同 miRNA 的靶标,包括 、 、 和 作为差异表达 miRNA 的直接靶标。鉴定患者来源神经元中改变的途径表明,这些调节网络的破坏可能导致 BP 中的复杂表型。