Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.
Genome Institute of Singapore, Singapore, Singapore.
PLoS Biol. 2019 Jun 6;17(6):e3000276. doi: 10.1371/journal.pbio.3000276. eCollection 2019 Jun.
The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.
神经干细胞 (NSC) 在静止和增殖之间转换的能力对于大脑发育和稳态至关重要。果蝇 Hippo 通路维持 NSC 静止，但它在大脑发育过程中的调节仍不清楚。在这里，我们表明进化保守的 E3 泛素连接酶 CRL4Mahj 对于 NSC 再激活（退出静止）是必需的。我们证明，受损的 DNA 结合蛋白 1 (DDB1) 和 Cullin4，Cullin4-RING 连接酶 (CRL4) 的两个核心组成部分，对于 NSC 再激活是内在必需的。我们已经鉴定出 CRL4 的底物受体 Mahjong (Mahj)，它对于 NSC 再激活是必需和充分的。此外，我们表明 CRL4Mahj 与 Hippo 信号通路的激酶 Warts (Wts/大肿瘤抑制因子 [Lats]) 形成蛋白复合物，并且 Mahj 促进 Wts 的泛素化。我们的遗传分析进一步支持这样的结论，即 CRL4Mahj 通过抑制 Wts 触发 NSC 再激活。鉴于 Cullin4B 突变导致智力迟钝和大脑畸形，类似的调节机制可能适用于人类大脑。
