Huang Tan, Fakurazi Sharida, Cheah Pike-See, Ling King-Hwa
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
Sci Rep. 2025 Jan 22;15(1):2818. doi: 10.1038/s41598-025-87314-y.
Increasing shreds of evidence suggest that neurogenic-to-gliogenic shift may be critical to the abnormal neurodevelopment observed in individuals with Down syndrome (DS). REST, the Repressor Element-1 Silencing Transcription factor, regulates the differentiation and development of neural cells. Downregulation of REST may lead to defects in post-differentiation neuronal morphology in the brain of the DS fetal. This study aims to elucidate the role of REST in DS-derived NPCs using bioinformatics analyses and laboratory validations. We identified and validated vital REST-targeted DEGs: CD44, TGFB1, FN1, ITGB1, and COL1A1. Interestingly, these genes are involved in neurogenesis and gliogenesis in DS-derived NPCs. Furthermore, we identified nuclear REST loss and the neuroblast marker, DCX, was downregulated in DS human trisomic induced pluripotent stem cells (hiPSCs)-derived NPCs, whereas the glioblast marker, NFIA, was upregulated. Our findings indicate that the loss of REST is critical in the neurogenic-to-gliogenic shift observed in DS-derived NPCs. REST and its target genes may collectively regulate the NPC phenotype.
越来越多的证据表明，神经源性向胶质源性转变可能是唐氏综合征（DS）患者异常神经发育的关键。REST，即阻遏元件1沉默转录因子，调节神经细胞的分化和发育。REST的下调可能导致DS胎儿大脑中分化后神经元形态的缺陷。本研究旨在通过生物信息学分析和实验室验证阐明REST在DS来源的神经前体细胞（NPCs）中的作用。我们鉴定并验证了重要的REST靶向差异表达基因（DEGs）：CD44、转化生长因子β1（TGFB1）、纤连蛋白1（FN1）、整合素β1（ITGB1）和I型胶原α1链（COL1A1）。有趣的是，这些基因参与了DS来源的NPCs中的神经发生和胶质发生。此外，我们发现DS人三倍体诱导多能干细胞（hiPSCs）来源的NPCs中存在核REST缺失，神经母细胞标志物双皮质素（DCX）下调，而成胶质细胞标志物核因子IA（NFIA）上调。我们的研究结果表明，REST的缺失在DS来源的NPCs中观察到的神经源性向胶质源性转变中至关重要。REST及其靶基因可能共同调节NPC表型。
