Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London, UK.
Nat Neurosci. 2010 Nov;13(11):1365-72. doi: 10.1038/nn.2644. Epub 2010 Oct 10.
Neural stem and progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes and oligodendrocytes. However, the mechanisms underlying the decision of a stem cell to either self-renew or differentiate are incompletely understood. We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate recognition component of an SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase, is a key regulator of NSC/NPC viability and differentiation. The absence of Fbw7 in the mouse brain caused severely impaired stem cell differentiation and increased progenitor cell death. Fbw7 deficiency resulted in accumulation of two SCF(Fbw7) substrates, the transcription factors active Notch1 and N-terminally phosphorylated c-Jun. Genetic and pharmacological rescue experiments identified c-Jun as a key substrate of Fbw7 in controlling progenitor cell viability, whereas inhibition of Notch signaling alleviated the block in stem cell differentiation. Thus Fbw7 controls neurogenesis by antagonizing Notch and c-Jun N-terminal kinase (JNK)/c-Jun signaling.
神经干细胞和祖细胞（NSCs/NPCs）分化为神经元、星形胶质细胞和少突胶质细胞。然而，干细胞自我更新或分化的决定机制尚未完全阐明。我们在此证明，Fbw7（F-box 和 WD 重复结构域蛋白 7）是 SCF（由 SKP1、CUL1 和 F-box 蛋白组成的复合物）型 E3 泛素连接酶的底物识别组件，是 NSC/NPC 存活和分化的关键调节因子。在小鼠大脑中缺乏 Fbw7 会严重损害干细胞的分化并增加祖细胞的死亡。Fbw7 缺失导致两种 SCF(Fbw7)底物，即转录因子活跃的 Notch1 和 N 端磷酸化的 c-Jun 的积累。遗传和药理学挽救实验确定 c-Jun 是 Fbw7 控制祖细胞活力的关键底物，而抑制 Notch 信号则缓解了干细胞分化的阻滞。因此，Fbw7 通过拮抗 Notch 和 c-Jun N 端激酶（JNK）/c-Jun 信号通路来控制神经发生。
