Elevated FOXG1 supports exit from quiescence in neural stem cells through FoxO6

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 upre...

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Bibliographic Details
Published inbioRxiv
Main Authors Ferguson, Kirsty M, Blin, Carla, Claudia Garcia Diaz, Bulstrode, Harry, Bressan, Raul, Mccarten, Katrina, Pollard, Steve
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.07.2022
Subjects
Cell cycle
Cell proliferation
Forebrain
Forkhead protein
Foxg1 protein
FOXO3 protein
Glioblastoma
Molecular modelling
Neural stem cells
Stem cells
Tumor suppressor genes
Tumors
Vacuoles
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Summary: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 in controlling the exit from quiescence in NSCs, and shed light on the functions of this underexplored FoxO family member. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.06.30.498283