A Mitochondrial Switch Regulates Stemness in Neural Milieu

Regulation of redox is central to maintenance of stemness in multicellular organisms. However, the underlying molecular mechanisms that underpin redox-mediated regulation of stemness remain largely unknown. Here, we report that mitochondrial by-products, GTP and reactive oxygen species (ROS), regulate the balance of stemness and differentiation during brain development by calibrating the output of a signalling network that incorporates an “AND logic”. The opportunity to decode redox-mediated regulation of stemness arose from the discovery that selective endocytosis of erythroblasts by neuroepithelial cells significantly accelerates neuronal differentiation compared to adjacent non-cannibalistic cells that share the same milieu. Erythroblastic heme accelerates the pace of neurogenesis by induction of a truncated neurogenic program from a poised differentiation state. Mechanistically, the poised state is invoked by activation of the mitochondrial electron transport chain that leads to amplified production of ROS in addition to omnipresent GTP with consequential upregulation of pro-differentiation β-catenin.