Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

Summary: In the dentate gyrus (DG) of the mouse hippocampus, neurogenesis and astrogliogenesis persist throughout life. Adult-born neurons and astrocytes originate from multipotent neural stem cells (NSCs) whose activity is tightly regulated within the neurogenic niche. However, the cell-intrinsic mechanisms controlling neuron-glia NSC fate choice are largely unknown. Here, we show COUP-TFI/NR2F1 expression in DG NSCs and its downregulation upon neuroinflammation. By using in vivo inducible knockout lines, a retroviral-based loss-of-function approach and genetic fate mapping, we demonstrate that COUP-TFI inactivation in adult NSCs and/or mitotic progenitors reduces neurogenesis and increases astrocyte production without depleting the NSC pool. Moreover, forced COUP-TFI expression in adult NSCs/progenitors decreases DG astrogliogenesis and rescues the neuro-astrogliogenic imbalance under neuroinflammation. Thus, COUP-TFI is necessary and sufficient to promote neurogenesis by suppressing astrogliogenesis. Our data propose COUP-TFI as a central regulator of the neuron-astroglia cell fate decision and a key modulator during neuroinflammation in the adult hippocampus. : The adult hippocampal dentate gyrus contains multipotent neural stem cells (NSCs) and neuronal committed progenitors. Bonzano et al. demonstrate that the nuclear receptor COUP-TFI cell-intrinsically drives NSCs/progenitors toward neurogenesis by repressing astrogliogenesis. Notably, COUP-TFI downregulation occurs in inflamed hippocampi, and its overexpression rescues the hippocampal neurogenesis-astrogliogenesis imbalance due to neuroinflammation. Keywords: adult neurogenesis, dentate gyrus, neuroinflammation, NR2F1, neural stem cells, neural progenitors, astrogliogenesis