Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun
Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun
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DOI：
10.1038/nn.2644
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发表时间：
2010-11-01
影响因子：
25
通讯作者：
Behrens, Axel
中科院分区：
文献类型：
--
作者：
Hoeck, Joerg D.;Jandke, Anett;Behrens, Axel
神经干细胞和祖细胞（NSCs/NPCs）可产生神经元、星形胶质细胞和少突胶质细胞。然而，干细胞决定自我更新还是分化的潜在机制尚未完全了解。在此我们证明，Fbw7（含F - 框和WD重复结构域蛋白7），一种SCF（由SKP1、CUL1和F - 框蛋白组成的复合物）型E3泛素连接酶的底物识别组分，是神经干细胞/祖细胞活力和分化的关键调节因子。小鼠大脑中Fbw7的缺失导致干细胞分化严重受损以及祖细胞死亡增加。Fbw7缺失导致两种SCF(Fbw7)底物，即转录因子活性Notch1和N端磷酸化的c - Jun积累。遗传和药理学挽救实验确定c - Jun是Fbw7在控制祖细胞活力方面的关键底物，而抑制Notch信号通路可缓解干细胞分化的阻滞。因此，Fbw7通过拮抗Notch和c - Jun N末端激酶（JNK）/c - Jun信号通路来控制神经发生。
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.