Abstract
miRNA miR-124 has been employed supplementary to neurogenic TFs and other miRNAs to enhance direct neurogenic conversion by suppressing multiple non-neuronal targets. Aim of the 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 towards an immature neuronal fate, by directly targeting the RNA-binding protein Zfp36l1 implicated in ARE-mediated mRNA decay and subsequently de-repressing 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 both miR-124-induced reprogramming efficiency and iNs’ functional maturation. Importantly, miR-124 is potent to guide direct conversion of reactive astrocytes to immature iNs of cortical identity in vivo following cortical trauma, confirming its ‘master’ reprogramming capacity within the injured cortical microenvironment, while ISX9 supplementation confers a survival advantage to newly produced iNs.
Significance statement Direct reprogramming protocols have employed miR-124 along with other neurogenic factors to support cell fate conversion. Here we have studied the ‘master reprogramming’ potential of miR-124 in the direct neurogenic conversion of astrocytes and show that the direct targeting of the abundant in astrocytes RNA binding protein Zfp36l1 is critical in conferring the astrocytic to neurogenic transcriptomic switch, leading to de-repression of Zfp36l1 neurogenic interactome and establishment of immature neuronal identity. Our data uncover a mechanism of miR-124 action during astrocytic reprogramming that recapitulates endogenous neurogenesis pathways, being further reinforced by addition of the neurogenic molecule ISX9 resulting in mature iNs’ production. Importantly, miR-124 exhibits in vivo reprogramming capacity in a cortical trauma model, further supporting its ‘master reprogramming’ potential.
Competing Interest Statement
The authors have declared no competing interest.
