Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrains NSCs to a self-renewing state and prevents neurosphere formation. Ncf1-dependent oxidation of Igfbp2 promotes neurogenesis by NSCs in vitro and in vivo while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1^–/– and Igfbp2^–/– NSCs favor the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induces DDSBs and is sufficient to rescue the ability of Ncf1^–/– and Igfbp2^–/– NSCs to lineage-commit to form neurospheres and neurons. NSC lineage commitment is dependent on the oxidizable cysteine-43 residue of Igfbp2. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.

神经干细胞 (NSC) 的维持和功能受活性氧 (ROS) 的调节。然而，ROS 控制 NSC 行为的机制仍不清楚。在这里，我们报告ROS依赖性Igfbp2信号传导控制DNA修复途径，平衡NSC自我更新和谱系承诺。 Ncf1或Igfbp2缺陷会限制 NSC 处于自我更新状态并阻止神经球形成。 Igfbp2 的 Ncf1 依赖性氧化可在体外和体内促进 NSC 的神经发生，同时抑制 Brca1 DNA 损伤反应基因并诱导 DNA 双链断裂 (DDSB)。相比之下， Ncf1 ^–/–和Igfbp2 ^–/– NSC 在体外和体内有利于少突胶质细胞的形成。值得注意的是，Brca1 DNA 修复途径基因的瞬时抑制会诱导 DDSB，并足以挽救Ncf1 ^–/–和Igfbp2 ^–/– NSC 谱系定向形成神经球和神经元的能力。 NSC 谱系定向取决于 Igfbp2 的可氧化半胱氨酸 43 残基。我们的研究强调了 DNA 损伤/修复在协调氧化还原调节的 Igfbp2 下游 NSC 命运决定中的作用。