Pang Yunli, Ruan Xiangbin, Liu Wei, Hou Lin, Yin Bin, Shu Pengcheng, Peng Xiaozhong
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
State Key Laboratory of Respiratory Health and Multimorbidity, Beijing 100005, China.
Int J Biol Sci. 2024 Nov 11;20(15):6207-6221. doi: 10.7150/ijbs.94739. eCollection 2024.
During cortical development, the differentiation potential of neural progenitor cells (NPCs) is one of the most critical steps in normal cortical formation and function. Defects in this process can lead to many brain disorders. MicroRNA dysregulation in the dorsolateral prefrontal cortex is associated with risk for a variety of developmental and psychiatric conditions. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we found that microRNA-495-3p (miR-495) is expressed in NPCs of the developing mouse cerebral cortex. Furthermore, aberrant expression of miR-495 promotes the formation of superficial neurons. Our results suggest that miR-495 can target transcription factor 4 (TCF4), a gene linked to the neurodevelopmental disorder Pitt-Hopkins syndrome (PTHS), to ensure normal differentiation of NPCs in the developing cerebral cortex. Furthermore, TCF4 loss-of-function and gain-of-function experiments show opposite effects on miR-495 regulation of neural progenitor differentiation potential. Together, these results demonstrated that miR-495 regulates cortical development through TCF4 for the first time.
在皮质发育过程中，神经祖细胞（NPCs）的分化潜能是正常皮质形成和功能的最关键步骤之一。这一过程中的缺陷会导致多种脑部疾病。背外侧前额叶皮质中的微小RNA失调与多种发育和精神疾病的风险相关。然而，这一过程背后的分子机制在很大程度上仍然未知。在本研究中，我们发现微小RNA-495-3p（miR-495）在发育中的小鼠大脑皮质的NPCs中表达。此外，miR-495的异常表达促进了浅层神经元的形成。我们的结果表明，miR-495可以靶向转录因子4（TCF4），该基因与神经发育障碍皮特-霍普金斯综合征（PTHS）相关，以确保发育中的大脑皮质中NPCs的正常分化。此外，TCF4功能丧失和功能获得实验对miR-495对神经祖细胞分化潜能的调节显示出相反的作用。总之，这些结果首次证明miR-495通过TCF4调节皮质发育。
