Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is actively involved in brain homeostasis. Thus, identification of novel regulators in adult neurogenesis could significantly contribute to new therapies. We have recently unraveled the regulatory role of NR5A2 (also known as LRH1), a druggable orphan nuclear receptor, in embryonic neurogenesis. However, its involvement in adult neurogenesis is still an open question. Here we show that NR5A2 is differentially expressed in the DG of the adult hippocampus with neurons exhibiting higher levels of expression than adult neural stem/progenitor cells (aNSCs), suggesting a correlation with neuronal differentiation. Notably, NR5A2 overexpression in ex vivo cultured aNSCs induces expression of Prox1, a critical regulator of adult hippocampal neurogenesis. In agreement, NR5A2 is sufficient to reduce proliferation, increase neuronal differentiation, and promote axon outgrowth. Moreover, depletion of NR5A2 in DG cells in vivo caused a decrease in the number of NeuN as well as Calbindin-positive neurons, indicating its necessity for the maintenance of neuronal identity. Our data propose a regulatory role of NR5A2 in neuronal differentiation and fate specification of adult hippocampal NSCs.

成年海马齿状回 (DG) 的神经发生积极参与脑稳态。因此，鉴定成人神经发生中的新调节剂可以显着促进新疗法。我们最近揭示了 NR5A2（也称为 LRH1）（一种可药物孤儿核受体）在胚胎神经发生中的调节作用。然而，它在成人神经发生中的参与仍然是一个悬而未决的问题。在这里，我们显示 NR5A2 在成年海马的 DG 中差异表达，神经元表现出比成年神经干/祖细胞 (aNSC) 更高的表达水平，表明与神经元分化相关。值得注意的是，NR5A2 在离体培养的 aNSCs 中过表达诱导Prox1 的表达，成人海马神经发生的关键调节剂。一致认为，NR5A2 足以减少增殖、增加神经元分化并促进轴突生长。此外，体内 DG 细胞中 NR5A2 的消耗导致 NeuN 和钙结合蛋白阳性神经元的数量减少，表明其对维持神经元身份的必要性。我们的数据提出了 NR5A2 在成年海马神经干细胞的神经元分化和命运规范中的调节作用。