FoxO3 Regulates Neural Stem Cell Homeostasis

Abstract

Summary In the nervous system, neural stem cells (NSC) are necessary for the generation of new neurons and for cognitive function. Here we show that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, regulates the NSC pool. We find that adult FoxO3−/− mice have fewer NSC in vivo than wild type counterparts. NSC isolated from adult FoxO3−/− mice have decreased self-renewal and an impaired ability to generate different neural lineages. Identification of the FoxO3-dependent gene expression profile in NSC suggests that FoxO3 regulates the NSC pool by inducing a program of genes that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. The ability of FoxO3 to prevent the premature depletion of NSC might have important implications for counteracting brain aging in long-lived species.

Epigenetic regulation of aging stem cells

“…Conditional deletion of FoxO1, FoxO3 and FoxO4 in the adult hematopoietic system, as well as germline deletion of the single FoxO3 gene, trigger a loss in long-term repopulating capacity of HSCs due to enhanced exit from quiescence, increased apoptosis and increased levels of reactive oxygen species (Miyamoto et al, 2007;Tothova and Gilliland 2007;Yalcin et al, 2008). FOXO transcription factors are also necessary for the maintenance of adult NSCs (Paik et al, 2009;Renault et al, 2009). Concomitant deletion of FoxO1, FoxO3 and FoxO4 in the brain leads to a depletion of the NSC pools in adult mice (Paik et al, 2009).…”

“…Concomitant deletion of FoxO1, FoxO3 and FoxO4 in the brain leads to a depletion of the NSC pools in adult mice (Paik et al, 2009). Highlighting the importance of the FOXO3 isoform in NSCs, mice with germline-and brain-specific deletion of FoxO3 alone show significant decreases in long-term label retaining cells, the proposed quiescent pool of NSCs (Renault et al, 2009). FOXO factors also function to control the neurogenic potential of NSCs (Paik et al, 2009;Renault et al, 2009).…”

“…Highlighting the importance of the FOXO3 isoform in NSCs, mice with germline-and brain-specific deletion of FoxO3 alone show significant decreases in long-term label retaining cells, the proposed quiescent pool of NSCs (Renault et al, 2009). FOXO factors also function to control the neurogenic potential of NSCs (Paik et al, 2009;Renault et al, 2009). FoxO3 À/À NSCs generate fewer multipotent neurospheres in vitro, with a specific defect in generation of neurons (Renault et al, 2009), whereas FoxO1/FoxO3/FoxO4 compound mutant mice show decreased adult neurogenesis in the SVZ (Paik et al, 2009).…”

Rôle des facteurs de transcription FoxO dans la maintenance des cellules souches

“…Nous montrons que FoxO1 est fortement exprimée dans les CSEh et dans les cellules ES murines (CSEm) indifférenciées (Figure 2) identifié (Figure 2). Au-delà du système hématopoïétique, FoxO3 intervient dans d'autres populations de cellules souches : l'invalidation de FoxO3 induit un défaut du pool des cellules souches neurales adultes, diminue leur autorenouvellement et leur capacité à se différencier en lignages neuronaux spécifiques [14,15] (Figure 2). (Figure 3).…”

The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence

“…Among their evolved adaptations are elaborate cellular protective programs that ensure stem cell integrity, tissue homeostasis, and organismal survival (Biteau, Hochmuth & Jasper, 2008; Brown et al., 2013; Ito et al., 2004; Rando, 2006; Renault et al., 2009; Rossi, Jamieson & Weissman, 2008; Rossi et al., 2007; Sahin & Depinho, 2010; Sperka, Wang & Rudolph, 2012; Walter et al., 2015). The mitochondrial unfolded protein response (UPR mt ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues (Berger et al., 2016; Mohrin et al., 2015; Zhang et al., 2016).…”