Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano 10043, Italy; Department of Life Sciences and Systems Biology, University of Turin, Turin 10123, Italy; Université Côte d'Azur (UCA) CNRS, Inserm, iBV, Nice 06108, France.
Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Orbassano 10043, Italy; Department of Life Sciences and Systems Biology, University of Turin, Turin 10123, Italy.
Cell Rep. 2018 Jul 10;24(2):329-341. doi: 10.1016/j.celrep.2018.06.044.
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.
在小鼠海马齿状回（DG）中，神经发生和星形胶质细胞发生贯穿一生都在持续。成年新生神经元和星形胶质细胞来源于多能神经干细胞（NSC），其活性在神经发生龛内受到严格调节。然而，控制神经元-胶质 NSC 命运选择的细胞内在机制在很大程度上尚不清楚。在这里，我们显示了 COUP-TFI/NR2F1 在 DG NSCs 中的表达及其在神经炎症时下调。通过使用体内诱导型敲除系、基于逆转录病毒的功能丧失方法和遗传命运图谱，我们证明了在成年 NSCs 和/或有丝分裂祖细胞中 COUP-TFI 的失活会减少神经发生并增加星形胶质细胞生成，而不会耗尽 NSC 池。此外，在成年 NSCs/祖细胞中强制表达 COUP-TFI 会减少 DG 星形胶质细胞发生，并在神经炎症下挽救神经-星形胶质细胞失衡。因此，COUP-TFI 是通过抑制星形胶质细胞发生来促进神经发生所必需和充分的。我们的数据表明 COUP-TFI 是神经元-星形胶质细胞命运决定的中枢调节剂，也是成年海马体神经炎症期间的关键调节剂。
