Foxg1 (formerly BF-1) is the only member of the forkhead G family. It is expressed in rapidly proliferating cell populations including the developing telencephalon where it regulates the rate of neurogenesis by keeping cells in a proliferative state . Indeed, the loss of Foxg1 results in premature cell cycle exit and in differentiation of neocortical neural progenitors. Contrary to its role in regulating progenitor cell differentiation, the action of Foxg1 on cell cycle exit is independent of its DNA-binding properties .
Foxg1 is strongly expressed in the postnatal and adult telencephalon within the two neurogenic areas, the SVZ of the lateral ventricle and the DG of the hippocampus . Haploinsufficiency for Foxg1 (Foxg1+/− mice) or deletion of Foxg1 during postnatal DG development by crossing the Foxg1fl/fl mice with a Frizzled9-CreER line (i.e., Foxg1-cKO mice) is associated with behavioral deficits (such as abnormal locomotion and contextual fear conditioning) consistent with hippocampal dysfunctions [47-49]. Indeed, Foxg1+/− and Foxg1-cKO mouse lines showed a marked reduction in size and an important malformation of the DG. This is associated with a failure of postnatal DG neurogenesis, characterized by a reduction in the number of NSCs [48, 50]. On the contrary, an overexpression of Foxg1 enhances neurogenesis. This effect is correlated with an increase of neurite outgrowth and an inhibition of gliogenesis . Foxg1 cooperates with Bmi-1 (polycomb complex protein) to maintain forebrain NSC self-renewal and multipotency  mainly by repressing p21 expression (Table 2) .
Table 2. Target genes of Fox transcription factor involved in adult neurogenesis
|Members||DNA binding consensus sequences||Target genes||Regulation (up or down )||Functional consequences||References|
|Foxg1||ATAAACAANWGTAAACA||p21Cip1||Maintains forebrain NSC selfrenewal, multipotency and increases proliferation.|||
|Foxj1||TTTTGTTTGTTTG||Ank-3, DNAI1, DNALI1, SPAG6, TEKT1/2||Maintain an intact ependymal niche organization. Enhance the expression of cilia genes during multiciliated cell differentiation process.|||
|Foxo3||GTAAACATGTTTAC||p27Kip1,||Induce cell cycle arrest and cell fate decision||[72-75]|
| || ||p21Cip1|| || || |
| || ||Cyclin D|| || |
| || ||ASCL1/MASH1||Blocks neuronal differentiation||[59, 76]|
|Foxo1||GTAAACATGTTTAC||Bim, Bax||Induce apoptosis|||
|Foxm1||CCCAGCTGACCCA||Cyclin A/B1, ATF2, cdc25a/b, Sox2||Promote cell cycle progression||[66, 78, 79]|
| || ||p21Cip1,||Promote cell cycle progression|||
| || ||p27Kip1|| || || |
Foxg1 is also required for the survival of adult postmitotic neurons. In Foxg1+/− mice, the reduced size of the DG is caused by a cell survival decrease rather than reduced proliferation or granule cell differentiation . Foxg1-cKO mice show an increased cell death exclusively in postmitotic neurons . Ectopic expression of FoxG1 blocks neuronal death, whereas suppression of its expression induces death in otherwise healthy neurons . To promote neuronal survival, Foxg1 cooperates with transducin-like enhancer of split 1 (TLE1) in a casein kinase 2- (CK2) and PI3K-Akt-dependent manner . Phosphorylation of TLE1 at serine 239 by CK2 and phosphorylation of Foxg1 by Akt at Thr-271 are necessary for their neuronal survival-promoting activity. The exact stoichiometry between TLE1 and Foxg1 remains to be elucidated, but Foxg1 needs to physically interact with TLE1 to promote neuronal survival .
Three Foxj members have been identified: Foxj1, Foxj2, and Foxj3. Foxj2 and Foxj3 are closely related and are widely expressed during embryonic development including the brain but nothing is known about their role during central nervous system (CNS) development [83, 84]. Foxj1 is specifically expressed in epithelial cells containing classical motile cilia, including ependymal cells in the adult SVZ [52, 53]. Cilia are microtubule-based filamentous organelles classified in two types: nonmotile or primary cilia, which occur as single entity per cell, and motile cilia . Primary cilia have widespread distribution in many cell types and play important roles in signal transduction. Motile cilia are usually present in large numbers exclusively in areas where a fluid movement is required. Notably, they contribute to ependymal cell differentiation and to migration of adult type-A progenitor cells from the SVZ toward the RMS [86, 87]. The targeted disruption of the mouse Foxj1 gene results mainly in left/right asymmetry with loss of motile cilia and flagella [52, 54].
In the postnatal/adult SVZ, the absence of Foxj1 is associated with defects in proliferation and differentiation resulting in severe OB dysgenesis . Foxj1 is necessary for the differentiation of ependymal cells. Indeed, Foxj1−/− mice that do not exhibit aberrant left/right asymmetry survive into early adulthood, but their ependymal cells fail to differentiate and the surface of the cerebral ventricles is devoid of motile cilia. As a consequence, these knockout mice exhibit hydrocephalus. The core of a cilium, the so-called axoneme consists of a stereotypically arranged set of microtubules that originates at the basal body, which is anchored in the cortical actin cytoskeleton. Defective ciliogenesis in the absence of Foxj1 may result from the inability of basal bodies to migrate and anchor to the apical cytoskeleton leading to subsequent failure of axonemal formation . Interestingly, primary cilia are normally present in Foxj1−/− mouse brains . Thus, Foxj1 appears to be necessary for the biogenesis of motile cilia but not primary cilia.
The massive disruption of postnatal neurogenesis observed in the Foxj1−/− OB could not exclusively be linked to the absence of ependymal cells differentiation. Indeed, Foxj1 induction leads to differentiation of a subset of Foxj1+ radial glia into Foxj1+ astrocytes. Foxj1+ cells exhibit neurogenic potential in vivo and in vitro, suggesting that—at least a subset of them—function as postnatal and adult NSCs . Furthermore, Foxj1-dependent maturation of the NSCs nonautonomously regulates progenitor proliferation in the SVZ. Altogether, these data support the hypothesis that Foxj1+ cells represent a subset of SVZ NSCs [53, 55].
The molecular mechanisms triggered downstream of Foxj1 in the adult brain remain largely unsolved. Foxj1 is a Shh-regulated gene in the neural tube  while it has been suggested to regulate expression and intracellular localization of ezrin [89, 90], a membrane-cytoskeleton linking factor implicated in establishing cell polarity in epithelial cells . Whether this is the case in the adult brain remains to be demonstrated. Recently, it has been shown that ankyrin-3 (Ank-3) expression is regulated by Foxj1 in the adult SVZ (Table 2) . Ank-3 is a large adaptor molecule that organizes lateral membrane domains in numerous different cell types . In the adult SVZ, Ank-3 is specifically colocalized with Foxj1 cell population, that is, the ependymal cell lineage including some radial-glial cells and ependymal cells. In addition, disruption of Foxj1/Ank-3 pathway in vivo results in a dramatic reduction of neuroblasts production and brain ventricular wall organization . Therefore, Foxj1/Ank-3 pathway is essential to maintain an intact ependymal niche organization and thus to allow a continuous production of newly generated neurons in the postnatal and adult brain.
Other Foxj1 regulatory factors have been identified. Indeed, it has been suggested that CP110 (centrosomal protein of 110 kDa), a centriolar-associated protein that blocks the ciliogenesis, may be important to allow Foxj1 to induce motile cilia biogenesis. When CP110 is overexpressed in Xenopus embryos, it inhibits ciliogenesis through ectopic expression Foxj1 . RFX3, a member of the regulatory factor X (RFX) family of transcription factors, is also one such regulator of Foxj1. RFX3 is a key player in the formation of motile cilia in mouse brain ependymal cell cultures and acts, at least by regulating Foxj1 expression, by binding to its promoter . In addition, RFX3 and Foxj1 share some common direct target genes, suggesting that both types of transcription factors co-operate to govern a specific motile ciliogenic program [93-95]. Indeed, a recent publication  has shown that RFX3, in association with Foxj1, induces the expression of the cilia-associated genes dynein axonemal intermediate chain 1, dynein axonemal light intermediate chain 1, sperm-associated antigen 6, Tektin 1, and Tektin 2 during multiciliated cell differentiation (Table 2).
In mammals, there are four Foxos transcription factors: Foxo1, Foxo3, Foxo4, and Foxo6, which are encoded by distinct genes. Foxo6 is structurally and functionally distinct from the other isoforms, which are closely related to each other. Among their many biological functions, Foxo proteins are implicated in regulation of apoptosis, cell cycle progression, and oxidative stress resistance. They are also implied in glucose metabolism and suppression of tumorigenesis, properties mainly regulated by Foxo1. In the brain, the Foxos family is implicated in the regulation of NSCs self-renewal, proliferation, and differentiation during embryonic and adult neurogenesis.
Foxo1, Foxo3, and Foxo6 are expressed in the adult murine brain, while Foxo4 has not been found . More specifically, Foxo1 and Foxo3 are broadly expressed in multiple cell types including adult multipotent progenitors in the two neurogenic areas [57, 58]. On the contrary, Foxo6 is particularly highly expressed in CA1 and CA3 areas of the hippocampus but not in the DG, and therefore has no role in adult neurogenesis .
The role of Foxo1 and Foxo3 has been documented by mouse models lacking one or both genes [56-58]. In Foxo3−/− or brain-specific conditional Foxo1/3/4 triple knockout mice, the brain is enlarged in perinatal stages with a premature burst in Neural Progenitor Cells (NPCs) proliferation, leading to their exhaustion and precocious significant decline of their pool, and finally to a lack of neurogenesis [57, 58]. The deletion of upstream regulators of Foxo3, in Igf1 (insulin-like growth factor 1) or Akt knockout mice, also results in the formation of smaller brains [98, 99]. On the contrary, enhanced activity of Foxo3, which may arise after insulin receptor/IGF signaling deficiency, leads to a loss of neural progenitors and increased apoptosis .
Foxo3 is responsible for cell cycle arrest by upregulating the CDK inhibitor p27Kip1 which blocks S phase progression through a direct inhibition of cyclinE/CDK2 and cyclinA/CDK2 complexes (Table 2) . PI3K/Akt pathway induces inhibitory phosphorylation of Foxo3 in NPCs, leading to a reduction in p27Kip1 expression. It has also been reported that Foxo3 induces p21Cip1 expression and represses cyclins D expression (G1/S arrest) or it activated cyclin G2 (G0/G1 arrest), leading to cell cycle arrest (Table 2) [73-75]. Interestingly, mice deficient for p21 also showed an increase in early proliferation of NSCs followed by an accelerated age-dependent loss of NSCs self-renewal , suggesting that a pool of NSCs is generated at birth and is not indefinitely produced.
Among the Foxo3-regulated genes in NPCs are enzymes in carbon metabolism that act to combat reactive oxygen species by directing the flow of glucose and glutamine carbon into defined metabolic pathways . In Foxo3 adult NPCs, an unexpected downregulation of glutamine and glucose metabolism occurred, that in turn leads to decreased pyruvate kinase and pentose phosphate pathway, respectively. These metabolic alterations contribute to a more oxidative cellular environment leading to accumulation of oxidative damage in Foxo3 KO NPCs.
More recently, it has been shown that Foxo3 maintains stemness and the NSCs pool in the adult niches by restraining master regulators of differentiated CNS cell fates . Indeed, FoxO3 inhibits ASCL1/Mash1-dependent neurogenesis. ASCL1/Mash1 is a basic helix-loop-helix transcription factor that has been shown to be essential for neural differentiation during adult neurogenesis (Table 2) [59, 76]. Interestingly, ASCL1/Mash1 protein stabilization has been shown to mediate some of the cellular action of the PI3K-AKT signaling on neurogenesis . Thus, it is conceivable that the PI3K-AKT signaling pathway coordinates ASCL1 stabilization with ASCL1 activation (via inhibition of the repressive effect of Foxo3 on ASCL1) to achieve a more potent induction of neurogenesis. How Foxo3 and ASCL1/Mash1 interact in vivo, and which ASCL1 transcriptional targets are inhibited remain to be established.
In the adult brain, Foxo1 has been identified as a key regulator of cell death. Activation of Foxo1 induces apoptosis by upregulating a number of cell death genes such as Bim or Bax (Table 2) . In neurons, CDK1 phosphorylates Foxo1, and thereby disrupts its interaction with 14-3-3 proteins, resulting in its nuclear localization and increasing its transcriptional activity . However, in Foxo1 knockout mice, no appreciable changes in apoptosis are observed both in NSCs and neurons .
Foxm1, also named Trident (mouse) or HFH-11B (human), binds promoter regions on a consensus “TAAACA” site similar to other forkhead proteins but with a unique affinity for tandem repeats. This may explain its relative low affinity for single copies of its forkhead consensus sequence . Alternative splicing of two exons gives rise to three isoforms of Foxm1, the transcriptionally active Foxm1b and Foxm1c, and the transcriptionally inactive Foxm1a splice variants . Foxm1 is a key regulator of the cell cycle, critical for G1/S phase transition and G2/M progression. Its expression and transcriptional activity depend on the progression of cell cycle and correlates with its phosphorylation level. Foxm1 protein and phosphorylation levels are diminished in quiescent cells, but both are upregulated during late G1-phase of the cell cycle and they persist throughout the G2- and M-phases [62, 106]. Foxm1 controls G1/S-phase transition by upregulating expression of several critical genes such as Cyclin A, activating transcription factor 2, and Cdc25A phosphatase, while downregulating protein levels of p21Cip1 and p27Kip1 through the activation of Skp2 and Cks1 genes (encoding subunits of the Skp1-Cullin1-F-box ubiquitin ligase complex) . During G2 phase, Foxm1 also increases the expression of Cyclin B1 and cdc25b genes, which are required for mitotic entry and completion (Table 2) .
Foxm1 is ubiquitously expressed in embryonic tissues, particularly in proliferating cells of epithelial or mesenchymal origin . Foxm1−/− mice die in utero between E13.5 and E17.5 due to multiple abnormalities in several organs including liver, lung, brain, and heart [63-65]. In adult tissues, FoxM1 expression is restricted to actively dividing cells and is eliminated in resting or terminally differentiating cells . Therefore, Foxm1 is a typical proliferation-associated transcription factor. In situ hybridization revealed that Foxm1 mRNAs are highly expressed in NSCs and neural precursor cells during embryonic development [67, 108] and in both neurogenic areas in adult CNS (personal observations).
Deletion of Foxm1 impairs the self-renewal of embryonic NSCs and loss of Foxm1 is correlated with a lack of Sox2 expression, which seems to be directly activated by Foxm1 . A conditional deletion of Foxm1 from precursors of cerebellar granule neurons (Math1-Cre and Nestin-Cre transgenes) caused delayed brain development . Indeed, Foxm1-deficient cerebellar granule neuron precursors showed a significant delay in the G2/M transition probably through decreased expression of the target genes cyclin B1 and Cdc25b (Table 2). Furthermore, Foxm1 is a component of the Wnt signaling pathway and Foxm1-beta-catenin interaction is required for the activation of the canonical Wnt signaling pathway in NSCs . Blockade of Wnt signaling reduces adult hippocampal neurogenesis both in vivo and in vitro. It is therefore tempting to speculate that Foxm1 is required for adult neurogenesis.