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.

The FoxO family of Forkhead transcription factors functions at the interface of tumor suppression, energy metabolism, and organismal longevity. FoxO factors are key downstream targets of insulin, growth factor, nutrient, and oxidative stress stimuli that coordinate a wide-range of cellular outputs. FoxO-dependent cellular responses include gluconeogenesis, neuropeptide secretion, atrophy, autophagy, apoptosis, cell cycle arrest, and stress resistance. This review will discuss the roles of the mammalian FoxO family in a variety of cell-types, from stem cells to mature cells, in the context of the whole organism. Given the overwhelming evidence that the FoxO factors promote longevity in invertebrates, this review will also discuss the potential role of the FoxO factors in the aging of mammalian organisms. A traditional view of FoxO regulation and cellular functionMammals have four isoforms of the FoxO transcription factor family, FoxO1, FoxO3, FoxO4 and FoxO6. Three of the four FoxO isoforms, FoxO1, FoxO3 and FoxO4, are crucially regulated by Akt-dependent phosphorylation at three specific sites in response to growth factor and insulin stimulation (Thr32, Ser253 and Ser315 for human FoxO3) [1][2][3][4]. Akt-dependent phosphorylation of FoxO factors promotes FoxO export from the nucleus to the cytoplasm, thereby repressing FoxO transcriptional function (Fig. 1A). FoxO6 lacks the C-terminal Aktdependent site and is thus predominantly nuclear, although the phosphorylation of the two remaining Akt-dependent sites inhibits FoxO6 transcriptional activity [5,6]. FoxO factors have emerged as a convergence point of signaling in response to growth factor stimulation and oxidative stress (Fig. 1) [1,[7][8][9][10][11][12]. Insulin and growth factors inhibit FoxO factors through PI3K/ Akt, while oxidative stress stimuli activate FoxO factors through a combination of modifications. In addition to the PI3K/Akt pathway, the other major signaling modules that directly regulate the activity of the FoxO factors include the stress-activated Jun-N-terminal kinase (JNK), the mammalian ortholog of the Ste20-like protein kinase (MST1), and the deacetylase Sirt1 (Fig. 1) [9][10][11][13][14][15]. The FoxO factors integrate these divergent signals through post-translational modifications, such as phosphorylation, acetylation and mono/polyubiquitination, resulting in altered subcellular localization, protein stability, DNA binding properties, and transcriptional activity [1,9,11,12,14,16]. FoxO-dependent transcription plays an important role in a wide variety of cellular outputs, including glucose metabolism, cell cycle arrest, differentiation, detoxification of reactive oxygen species (ROS), repair of damaged DNA, and apoptosis [17][18][19][20][21][22][23][24][25][26].2 corresponding author Tel: +1 650 725 8042, FAX: +1 650 725 1534, email: anne.brunet@stanford.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early ver...

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.

The insulin-like growth factors (IGFs) are essential for development; bioavailable IGF is tightly regulated by six related IGF-binding proteins (IGFBPs). Igfbp5 is the most conserved and is developmentally up-regulated in key lineages and pathologies; in vitro studies suggest that IGFBP-5 functions independently of IGF interaction. Genetic ablation of individual Igfbps has yielded limited phenotypes because of substantial compensation by remaining family members. Therefore, to reveal Igfbp5 actions in vivo, we generated lines of transgenic mice that ubiquitously overexpressed Igfbp5 from early development. Significantly increased neonatal mortality, reduced female fertility, whole-body growth inhibition, and retarded muscle development were observed in Igfbp5-overexpressing mice. The magnitude of the response in individual transgenic lines was positively correlated with Igfbp5 expression. Circulating IGFBP-5 concentrations increased a maximum of only 4-fold, total and free IGF-I concentrations increased up to 2-fold, and IGFBP-5 was detected in high Mr complexes; however, no detectable decrease in the proportion of free IGF-I was observed. Thus, despite only modest changes in IGF and IGFBP concentrations, the Igfbp5-overexpressing mice displayed a phenotype more extreme than that observed for other Igfbp genetic models. Although growth retardation was obvious prenatally, maximal inhibition occurred postnatally before the onset of growth hormone-dependent growth, regardless of Igfbp5 expression level, revealing a period of sensitivity to IGFBP-5 during this important stage of tissue programming.T he insulin-like growth factors (IGF-I and -II) are essential for growth and development (1). Six high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6; refs. 2 and 3) strictly orchestrate IGF action. Despite their considerable sequence homology, each exhibits a discrete expression pattern and possesses an individual subset of motifs, signifying that although IGFBPs have common actions, they may also have unique properties.IGFBP-5 is the most conserved of the IGFBPs (4) and has been highlighted as a focal regulatory factor during the development of several key cell lineages, e.g., myoblasts (5) and neural cells (6, 7). In mice, Igfbp5 is expressed in the embryo from early development, principally in the myotomal component of the somites and developing central nervous system (8). Postnatally, serum IGFBP-5, in common with IGFBP-3, forms a ternary complex with IGF-I or IGF-II and the acid-labile subunit (9). Igfbp5 is up-regulated in the aggressive pediatric cancer, rhabdomyosarcoma (10), in the progression of prostate cancers to androgen independence (11), and in smooth muscle-derived uterine leiomyoma (12), indicating a function in neoplasia.IGFBP-5 initially binds IGFs with high affinity, principally by an N-terminal motif (13), and inhibits IGF activity by preventing IGF interaction with the type 1 receptor. It is further subject to regulated posttranslational modifications (3) to induce conformational changes that dec...