细胞周期异质性决定了神经干细胞从静止状态激活的时间。
Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence.
作者信息
Otsuki L, Brand A H
机构信息
The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
出版信息
Science. 2018 Apr 6;360(6384):99-102. doi: 10.1126/science.aan8795.
Abstract
Quiescent stem cells in adult tissues can be activated for homeostasis or repair. Neural stem cells (NSCs) in are reactivated from quiescence in response to nutrition by the insulin signaling pathway. It is widely accepted that quiescent stem cells are arrested in G In this study, however, we demonstrate that quiescent NSCs (qNSCs) are arrested in either G or G G-G heterogeneity directs NSC behavior: G qNSCs reactivate before G qNSCs. In addition, we show that the evolutionarily conserved pseudokinase Tribbles (Trbl) induces G NSCs to enter quiescence by promoting degradation of Cdc25 and that it subsequently maintains quiescence by inhibiting Akt activation. Insulin signaling overrides repression of Akt and silences transcription, allowing NSCs to exit quiescence. Our results have implications for identifying and manipulating quiescent stem cells for regenerative purposes.
摘要
成体组织中的静止干细胞可被激活以维持体内平衡或进行修复。大脑中的神经干细胞（NSCs）会通过胰岛素信号通路响应营养从静止状态重新激活。普遍认为静止干细胞停滞在G期。然而，在本研究中，我们证明静止神经干细胞（qNSCs）停滞在G1或G2期。G1-G2异质性指导神经干细胞行为：G1期qNSCs比G2期qNSCs更早重新激活。此外，我们表明进化上保守的假激酶Tribbles（Trbl）通过促进Cdc25降解诱导G2期神经干细胞进入静止状态，随后通过抑制Akt激活维持静止状态。胰岛素信号通路克服对Akt的抑制并使Trbl转录沉默，使神经干细胞退出静止状态。我们的结果对于识别和操纵静止干细胞用于再生目的具有重要意义。
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本文引用的文献
1
The pattern of proliferation of the neuroblasts in the wild-type embryo of Drosophila melanogaster.黑腹果蝇野生型胚胎中神经母细胞的增殖模式。
Rouxs Arch Dev Biol. 1987 Dec;196(8):473-485. doi: 10.1007/BF00399871.
2
Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease.21世纪的 Tribbles：Tribbles 假激酶在生物学和疾病中的角色演变
Trends Cell Biol. 2017 Apr;27(4):284-298. doi: 10.1016/j.tcb.2016.11.002. Epub 2016 Nov 28.
3
Neural stem cell-encoded temporal patterning delineates an early window of malignant susceptibility in Drosophila.神经干细胞编码的时间模式描绘了果蝇恶性易感性的早期窗口。
Elife. 2016 Jun 14;5:e13463. doi: 10.7554/eLife.13463.
4
Lineage mapping identifies molecular and architectural similarities between the larval and adult Drosophila central nervous system.谱系追踪揭示了果蝇幼虫和成虫中枢神经系统之间的分子和结构相似性。
Elife. 2016 Mar 15;5:e13399. doi: 10.7554/eLife.13399.
5
Transient nuclear Prospero induces neural progenitor quiescence.瞬时核蛋白Prospero诱导神经祖细胞静止。
Elife. 2014 Oct 29;3:e03363. doi: 10.7554/eLife.03363.
6
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PLoS One. 2014 Oct 15;9(10):e109530. doi: 10.1371/journal.pone.0109530. eCollection 2014.
7
A GAL4 driver resource for developmental and behavioral studies on the larval CNS of Drosophila.用于果蝇幼虫中枢神经系统发育和行为研究的GAL4驱动资源。
Cell Rep. 2014 Aug 7;8(3):897-908. doi: 10.1016/j.celrep.2014.06.065. Epub 2014 Jul 31.
8
Gap junction proteins in the blood-brain barrier control nutrient-dependent reactivation of Drosophila neural stem cells.血脑屏障中的缝隙连接蛋白控制果蝇神经干细胞的营养依赖性再激活。
Dev Cell. 2014 Aug 11;30(3):309-21. doi: 10.1016/j.devcel.2014.05.021. Epub 2014 Jul 24.
9
Fly-FUCCI: A versatile tool for studying cell proliferation in complex tissues.Fly-FUCCI：一种用于研究复杂组织中细胞增殖的多功能工具。
Cell Rep. 2014 Apr 24;7(2):588-598. doi: 10.1016/j.celrep.2014.03.020. Epub 2014 Apr 13.
10
Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells.无需细胞分离即可进行细胞类型特异性的基因表达和染色质结合分析：检测神经干细胞中 RNA 聚合酶 II 的占有率。
Dev Cell. 2013 Jul 15;26(1):101-12. doi: 10.1016/j.devcel.2013.05.020. Epub 2013 Jun 20.
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