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BMP 信号在成体海马祖细胞谱系的多个阶段调节其成熟的节奏。

BMP signaling regulates the tempo of adult hippocampal progenitor maturation at multiple stages of the lineage.

机构信息

Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.

出版信息

Stem Cells. 2014 Aug;32(8):2201-14. doi: 10.1002/stem.1688.

Abstract

Novel environmental stimuli, such as running and learning, increase proliferation of adult hippocampal neural stem cells (NSCs) and enlarge the population of new neurons. However, it remains unclear how increased numbers of new neurons can be generated in a time frame far shorter than the time required for proliferating stem cells to generate these neurons. Here, we show that bone morphogenetic protein (BMP) signaling in the subgranular zone regulates the tempo of neural progenitor cell (NPC) maturation by directing their transition between states of quiescence and activation at multiple stages along the lineage. Virally mediated overexpression of BMP4 caused NPC cell cycle exit and slowed the normal maturation of NPCs, resulting in a long-term reduction in neurogenesis. Conversely, overexpression of the BMP inhibitor noggin promoted NPC cell cycle entry and accelerated NPC maturation. Similarly, BMP receptor type 2 (BMPRII) ablation in Ascl1(+) intermediate NPCs accelerated their maturation into neurons. Importantly, ablation of BMPRII in GFAP(+) stem cells accelerated maturation without depleting the NSC pool, indicating that an increased rate of neurogenesis does not necessarily diminish the stem cell population. Thus, inhibition of BMP signaling is a mechanism for rapidly expanding the pool of new neurons in the adult hippocampus by tipping the balance between quiescence/activation of NPCs and accelerating the rate at which they mature into neurons.

摘要

新的环境刺激,如跑步和学习,会增加成年海马神经干细胞(NSC)的增殖,并扩大新神经元的数量。然而,目前尚不清楚在比增殖干细胞产生这些神经元所需的时间短得多的时间内,如何能够产生更多的新神经元。在这里,我们表明,在颗粒下区的骨形态发生蛋白(BMP)信号通过在谱系的多个阶段指导其在静止和激活状态之间的转变,调节神经祖细胞(NPC)成熟的节奏。病毒介导的 BMP4 过表达导致 NPC 细胞周期退出并减缓 NPC 的正常成熟,导致长期神经发生减少。相反,BMP 抑制剂 noggin 的过表达促进 NPC 细胞周期进入并加速 NPC 成熟。同样,Ascl1(+)中间 NPC 中的 BMP 受体型 2(BMPRII)缺失加速了它们向神经元的成熟。重要的是,GFAP(+)干细胞中 BMPRII 的缺失加速了成熟而不耗尽 NSC 池,表明神经发生的增加速度不一定会减少干细胞群体。因此,抑制 BMP 信号是通过在 NPC 的静止/激活之间平衡并加速它们向神经元成熟的速度,迅速扩大成年海马体中新神经元池的一种机制。

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