Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Neuropathol Appl Neurobiol. 2021 Oct;47(6):796-811. doi: 10.1111/nan.12717. Epub 2021 Jun 14.
Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a.
We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection.
The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1.
MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.
结节性硬化症（TSC）是一种与雷帕霉素靶蛋白复合物 1（mTORC1）信号通路失调相关的遗传疾病。神经发育障碍常存在于 TSC 中，与大脑中的皮质结节有关。我们之前报道过 microRNA-34a（miR-34a）是在结节中上调最多的 miRNAs 之一。在这里，我们研究了 miR-34a 在结节中的表达，重点关注早期脑发育，并评估了 miR-34a 对 mTORC1 通路和皮质发生的调节作用。
我们分析了 37 例切除的皮质结节（n=37）与尸检来源的对照组织（n=27）中的 miR-34a 表达。在 E18 时，评估了 miR-34a 过表达对皮质发生的影响。在 3 例 TSC 患者的原代星形胶质细胞培养物和转染 miR-34a 后的 SH-SY5Y 细胞中，评估了 mTORC1 通路的调节和生物信息预测的靶基因的表达。
在结节中，miR-34a 的表达高峰出现在婴儿期，同时存在病理标志物，特别是在巨细胞和畸形神经元中。miR-34a 在胎儿 TSC 皮质中也有强烈表达。在小鼠胚胎中过表达 miR-34a 会降低迁移到皮质板的细胞比例。miR-34a 模拟物的转染在 TSC 星形胶质细胞中负调节 mTORC1，并降低靶基因 RAS 相关（RRAS）和 NOTCH1 的表达。
miR-34a 在胎儿和出生后早期脑发育过程中在结节中表达最高。miR-34a 可以负调节 mTORC1；然而，它也可能导致 TSC 中的皮质发生异常。
