Gα Subunit Coordinates with Ephrin-B to Balance Self-Renewal and Differentiation in Neural Progenitor Cells

Proper development of the mammalian brain requires that neural progenitor cells balance self-renewal and differentiation under precise temporal and spatial regulation, but the underlying mechanisms are not well understood. In this study, we identify G alpha subunit as a positive regulator of mammalian neurogenesis, working with the regulator of G protein signaling (RGS)-mediated ephrin-B signaling pathway as two opposing forces to maintain a balance between self-renewal and differentiation in the developing mouse cerebral cortex. Multiple G alpha(i) subunits are expressed by cortical neural progenitor cells during the course of cortical neurogenesis. Activation of G alpha(i) signaling, through in utero electroporation-mediated expression of wild-type and constitutively active G alpha(i) subunits, counteracts the function of ephrin-B in cortical neural progenitors to induce differentiation. Genetic knock-in of an RGS-insensitive G184SG alpha(i2) causes early cell cycle exit and a reduction of cortical neural progenitor cells and leads to a defect in the production of late born cortical neurons, similar to what is observed in mutant mice with deficiency in ephrin-B reverse signaling pathway. This study reveals a role of Ga subunit in mammalian neurogenesis and uncovers a developmental mechanism, coordinated by the Ga and ephrin-B signaling pathways, for control of the balance between self-renewal and differentiation in neural progenitor cells. STEM CELLS 2010;28:1581-1589