Modelling quiescence exit of neural stem cells reveals a FOXG1-FoxO6 axis.

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-11-05 DOI:10.1242/dmm.052005
Kirsty M Ferguson, Carla Blin, Claudia Garcia-Diaz, Harry Bulstrode, Raul Bardini Bressan, Katrina McCarten, Steven M Pollard
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Abstract

The molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates FoxO6, a more recently discovered FoxO family member with potential oncogenic functions. Although genetic ablation of FoxO6 in proliferating NSCs has no effect on the cell cycle or entry into quiescence, we find that FoxO6-null NSCs can no longer efficiently exit quiescence following FOXG1 elevation. Increased FoxO6 results in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FoxO6, downstream of GBM-associated elevated FOXG1, in controlling quiescence exit, and shed light on the potential functions of this underexplored FoxO family member.

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神经干细胞静止退出模型揭示了 FOXG1-FoxO6 轴。
控制成体神经干细胞(NSCs)静止与增殖平衡的分子机制在胶质母细胞瘤(GBM)等脑癌中经常被失调。此前,我们曾报道,FOXG1是一种受前脑限制的神经发育转录因子,经常在胶质母细胞瘤干细胞(GSCs)中上调,并部分通过抑制肿瘤抑制因子Foxo3来限制细胞抑制途径的作用。在这里,我们发现FOXG1的增加会上调FoxO6,这是最近发现的具有潜在致癌功能的FoxO家族成员。虽然在增殖的 NSCs 中基因消减 FoxO6 对细胞周期或进入静止期没有影响,但我们发现 FoxO6 缺失的 NSCs 在 FOXG1 升高后不能再有效地退出静止期。FoxO6 的增加会导致大型酸性空泡的形成,这让人联想到 Pak1 调控的巨细胞吞噬作用。同样,在增殖性 NSCs 中,FOXG1 过表达会上调 Pak1 的表达,而 FoxO6 缺失则会下调 Pak1 的表达。这些数据表明,FoxO6 在与 GBM 相关的 FOXG1 升高的下游控制静止期的退出中起着促致癌的作用,并揭示了这一未被充分探索的 FoxO 家族成员的潜在功能。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
期刊最新文献
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