STAT3 REGULATES NEURAL PROGENITOR PROLIFERATION AND DIFFERENTIATION THROUGH MITOCHONDRIAL METABOLISM

Abstract

Upon transition from neuroepithelial cells, radial glia divide asymmetrically to self-renew and generate neurons or IPCs. After this neurogenesis stage, radial glia migrate basally and transform into glial progenitors. STAT3 was firstly found to be necessary for astrocyte differentiation of neural progenitors. During neurogenesis stage, its activation by IL6 family cytokines promotes proliferation while suppressing neurogenesis. However, the molecular mechanism of how STAT3 regulates neural progenitor self-renewal and differentiation remain unclear. This study utilized RNA-sequencing to reveal STAT3 target genes in neural progenitors. Here we showed that STAT3 is necessary for normal neurogenesis, while the loss of STAT3 promotes cell proliferation. STAT3 regulates expression of genes related to several metabolism pathways, especially the mitochondrial metabolism. STAT3 directly promotes the expression of genes involved in oxidative phosphorylation during neural progenitor development. Subsequently, STAT3 promotes mitochondrial respiration and negatively regulates ROS production. Finally, Stat3 cKO promotes neural progenitor proliferation through mitochondrial metabolism and activation of ROS signaling and the AMPK pathway.