A miR-124-mediated post-transcriptional mechanism controlling the cell fate switch of astrocytes to induced neurons

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 reprogram-ming 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 inter-actome. 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.

Automated summary

The study aims to investigate the role of miR-124 in driving direct reprogramming of astrocytes to induced neurons (iNs) and to elucidate its independent mechanism of action. The results show that miR-124 can directly target the RNA-binding protein Zfp36L1, which is involved in ARE-mediated mRNA decay, and derepress the neurogenic interactome of Zfp36L1, thus promoting the reprogramming of astrocytes towards an immature neuronal fate. Additionally, the addition of the neurogenic compound ISX9 enhances the effect of miR-124 on inducing neurogenesis. Importantly, miR-124 plays a significant role in guiding the direct conversion of reactive astrocytes to immature iNs in vivo after cortical trauma, and ISX9 supplementation improves the survival of newly produced iNs.