Neural Stem Cells and Neuroimaging Group, Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
DIANA-Lab, Hellenic Pasteur Institute & Department of Computer Science and Biomedical Informatics, University of Thessaly, Larissa, Greece.
Stem Cell Reports. 2023 Apr 11;18(4):915-935. doi: 10.1016/j.stemcr.2023.02.009. Epub 2023 Mar 23.
The microRNA (miRNA) miR-124 has been employed supplementary to neurogenic transcription factors (TFs) and other miRNAs to enhance direct neurogenic conversion. The aim of this study was to investigate whether miR-124 is sufficient to drive direct reprogramming of astrocytes to induced neurons (iNs) on its own and elucidate its independent mechanism of reprogramming action. Our data show that miR-124 is a potent driver of the reprogramming switch of astrocytes toward an immature neuronal fate by directly targeting the RNA-binding protein Zfp36L1 implicated in ARE-mediated mRNA decay and subsequently derepressing Zfp36L1 neurogenic interactome. To this end, miR-124 contribution in iNs' production largely recapitulates endogenous neurogenesis pathways, being further enhanced upon addition of the neurogenic compound ISX9, which greatly improves iNs' differentiation and functional maturation. Importantly, miR-124 is potent in guiding direct conversion of reactive astrocytes to immature iNs in vivo following cortical trauma, while ISX9 supplementation confers a survival advantage to newly produced iNs.
微 RNA（miRNA）miR-124 已被用于辅助神经发生转录因子（TFs）和其他 miRNA，以增强直接神经发生转化。本研究旨在探讨 miR-124 是否能够仅凭自身驱动星形胶质细胞向诱导神经元（iNs）的直接重编程，并阐明其独立的重编程作用机制。我们的数据表明，miR-124 通过直接靶向参与 ARE 介导的 mRNA 降解的 RNA 结合蛋白 Zfp36L1，是星形胶质细胞向不成熟神经元命运重编程开关的强大驱动因素，随后解除 Zfp36L1 神经发生相互作用体的抑制。为此，miR-124 对 iNs 产生的贡献在很大程度上再现了内源性神经发生途径，在添加神经发生化合物 ISX9 后进一步增强，这大大促进了 iNs 的分化和功能成熟。重要的是，miR-124 能够在皮质损伤后引导活性星形胶质细胞向不成熟的 iNs 进行直接转化，而 ISX9 的补充赋予新产生的 iNs 生存优势。
