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

Abstract

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 invivo following cortical trauma, while ISX9 supplementation confers a survival advantage to newly produced iNs.