FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis.
The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.
Paik
Ji-hye
JH
Department of Medical Oncology, Belfer Institute for Applied Cancer Science, Harvard Medical School, Boston, MA 02115, USA.
Ding
Zhihu
Z
Narurkar
Rujuta
R
Ramkissoon
Shakti
S
Muller
Florian
F
Kamoun
Walid S
WS
Chae
Sung-Suk
SS
Zheng
Hongwu
H
Ying
Haoqiang
H
Mahoney
Jed
J
Hiller
David
D
Jiang
Shan
S
Protopopov
Alexei
A
Wong
Wing H
WH
Chin
Lynda
L
Ligon
Keith L
KL
DePinho
Ronald A
RA
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002148:Calmodulin-Binding Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009929:Organ Size / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics
C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D010100:Oxygen