Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Institute of Translational Research, Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, The School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Cell Rep. 2021 Nov 2;37(5):109912. doi: 10.1016/j.celrep.2021.109912.
Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.
胎儿生长受限（FGR）增加了日后认知功能受损的风险。然而，确切的机制仍难以捉摸。通过使用地塞米松诱导的 FGR 和蛋白质限制影响的 FGR 小鼠模型，我们观察到成年 FGR 后代的学习和记忆缺陷。FGR 通过减少神经干细胞（NSC）的增殖，从出生后早期到成年期诱导海马神经发生减少。我们进一步发现 FGR 小鼠海马 NSC 中 Tet1 表达持续下降。从机制上讲，Tet1 下调导致 Dll3 和 Notch1 启动子的超甲基化和 Notch 信号抑制，导致 NSC 增殖减少。Tet1 的过表达激活 Notch 信号，抵消神经发生的下降，增强 FGR 后代的学习和记忆能力。我们的数据表明，海马 NSC 中 Tet1/Notch 信号的长期下降导致 FGR 后神经发生受损，可能成为干预与 FGR 相关认知障碍的潜在靶点。
