FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis

Department of Medical Oncology, Belfer Institute for Applied Cancer Science, Harvard Medical School, Boston, MA 02115, USA.
Cell stem cell (Impact Factor: 22.27). 11/2009; 5(5):540-53. DOI: 10.1016/j.stem.2009.09.013
Source: PubMed


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.

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    • "FoxO transcription factors have not only been found to regulate cell-cycle inhibitors, DNA-repair proteins , and detoxifying enzymes (van der Vos and Coffer 2011), but also have been shown to modulate signaling pathways regulating adult neural stem cells. These include the TGF-b (Seoane et al. 2004), Wnt (Essers et al. 2005; Paik et al. 2009), and Notch (Kitamura et al. 2007) signaling pathways. A recent ChIP-Seq analysis of adult neural stem/progenitor cells revealed that FoxO3 shares numerous targets with the bHLH transcription factor Mash1/Ascl1 with a conspicuous enrichment at the enhancers of genes involved in proneurogenic pathways (see below) (Webb et al. 2013). "
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    • "The FoxO proteins are currently the best-studied TFs promoting quiescence in NSCs. In mice mutant for FoxO1, FoxO3, and FoxO4 or for FoxO3 alone, an initial excess of NSC proliferation is followed by a depletion of the NSC pool and a decline in neurogenesis (Paik et al. 2009; Renault et al. 2009). Whether other TFs act downstream from quiescence-promoting signals and regulate common or distinct aspects of the physiology of quiescent NSCs is not known. "

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    • "Reduced self-renewal potential assessed by in vitro neurosphere formation assay and differentiation potential was also observed in FoxO deleted mice. In the absence of FoxO, NSCs undergo increased oxidative stress, altered glucose metabolism (Renault et al., 2009), and elevated Wnt signaling (Paik et al., 2009). This suggests that the FoxO family regulates homeostasis of NSC through regulation of diverse genes and pathways. "
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