**3. Signalling cascades regulating NPC fate under basal conditions**

NPCs from the dentate gyrus and SVZ have the potential to differentiate into neurons and glial cells. Multiple signalling pathways are activated to produce a neuron from NSCs. These cascades can involve both intrinsic and extrinsic factors as the NSC is created, mi‐ grates, and finally integrates into its final location.

#### **3.1. Proliferation and neuronal fate**

Many pathways important for embryonic neural development are conserved in adult neuro‐ genesis. The Wnt pathway, for example, is a key regulator of proliferation and differentiation in development and a key regulator of adult hippocampal neurogenesis [8]. Wnt signalling re‐ sults in the activation of the GSK3β/β-catenin that leads to the increased expression of Neu‐ roD1 and promotes neuronal differentiation in NSCs [9]. Activation of Wnt, Sonic Hedgehog (Shh), Notch, and the Sox family of genes, in particular *Sox2*, are also important for the forma‐ tion and proliferation of NSCs [10-12]. At early stages of differentiation, *Sox2* is required for neuronal fate; while downregulation of *Sox9* by miR-124 is required for neuronal differentia‐ tion [13, 14]. Other Sox members are important for neuronal specification, including *Sox3, Sox 4* and *Sox 11* [15-19]. Notch signalling is important for maintaining NSCs/NPCs, however this is dependent on the mitotic state of NSCs/NPCs [20]. Bone morphogenic protein (BMP) signal‐ ling inhibits neuronal differentiation; however expression of noggin and neurogenin-1 (Ngn1) in the SVZ and SGZ can obstruct this cascade [21-23]. Inhibition of the BMP pathway increases neurogenesis initially, however it results in depletion of the NSC pool leading to decreased neurogenesis [24]. In the dentate gyrus, the RNA-binding protein FXR2 regulates neurogene‐ sis by reducing the stability of noggin mRNA leading to an increased activation of the BMP pathway [25]. Proliferation in the SVZ is under epigenetic control via histone HZAX phoso‐ phorylation which can limit proliferation and overall neurogenesis [26].

**2. Adult neurogenesis**

**2.2. SVZ neurogenesis**

**2.1. Hippocampal neurogenesis**

242 Trends in Cell Signaling Pathways in Neuronal Fate Decision

tions with CA3 pyramidal neurons [4].

grates, and finally integrates into its final location.

**3.1. Proliferation and neuronal fate**

NPCs in the SGZ become neurons of the granular cell layer of the dentate gyrus in the hip‐ pocampus. In the SGZ, the most immature NPCs (Type 1) are radial and horizontal NPCs that transition to intermediate progenitors (type-2a, 2b and 3) and then to immature granule neurons which become dentate granular neurons. These then make large mossy fibre projec‐

The SVZ produces NPCs that form neuroblasts which migrate along the rostral migratory stream and become neurons in the olfactory bulb. These new neurons primarily become GA‐ BAergic granule neurons that provide lateral inhibition between mitral and tufted cells. A mi‐ nority of the new neurons become periglomerular neurons that are involved in lateral inhibition between glomeruli, and a small number of these cells are dopaminergic. Similar to the SGZ, there is a progression of NPC development in the SVZ. Slowly proliferating astro‐ cytes in the SVZ (Type B cells) are the NSCs and these generate the highly proliferative transitamplifying Type C cells. These then generate post-mitotic neuroblasts (the Type A cells) destined for the olfactory bulb via migration along the rostral migratory stream (RMS) [5-7].

**3. Signalling cascades regulating NPC fate under basal conditions**

NPCs from the dentate gyrus and SVZ have the potential to differentiate into neurons and glial cells. Multiple signalling pathways are activated to produce a neuron from NSCs. These cascades can involve both intrinsic and extrinsic factors as the NSC is created, mi‐

Many pathways important for embryonic neural development are conserved in adult neuro‐ genesis. The Wnt pathway, for example, is a key regulator of proliferation and differentiation in development and a key regulator of adult hippocampal neurogenesis [8]. Wnt signalling re‐ sults in the activation of the GSK3β/β-catenin that leads to the increased expression of Neu‐ roD1 and promotes neuronal differentiation in NSCs [9]. Activation of Wnt, Sonic Hedgehog (Shh), Notch, and the Sox family of genes, in particular *Sox2*, are also important for the forma‐ tion and proliferation of NSCs [10-12]. At early stages of differentiation, *Sox2* is required for neuronal fate; while downregulation of *Sox9* by miR-124 is required for neuronal differentia‐ tion [13, 14]. Other Sox members are important for neuronal specification, including *Sox3, Sox 4* and *Sox 11* [15-19]. Notch signalling is important for maintaining NSCs/NPCs, however this is dependent on the mitotic state of NSCs/NPCs [20]. Bone morphogenic protein (BMP) signal‐ ling inhibits neuronal differentiation; however expression of noggin and neurogenin-1 (Ngn1) Proneural proteins, basic-helix-loop-helix (bHLH) transcription factors also control neuronal fate commitment of NPCs. Type C cells of the SVZ fated to become GABAergic interneurons in the olfactory bulb express *Ascl1* [27]. *Ngn2* and *Tbr2* are expressed in dorsal SVZ progeni‐ tors that become glutamatergic juxtaglomerular neurons [28], while *Sp8* is required for par‐ valbumin-expressing interneurons in the olfactory bulb [29]. In the SGZ, *Neurog2* and *Tbr2* are expressed in NPCs destined to become glutamatergic neurons in the hippocampus [27, 30, 31], while over-expression of *Ascl1* produces oligodendrocytes [32].

Neurotrophic growth factors have been studied extensively in the SVZ. Many, including, epidermal growth factor (EGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF) can augment SVZ progenitor proliferation and migration of newly de‐ rived cells into structures beside the lateral ventricles; however these cells primarily differ‐ entiate into oligodendrocytes [33-36]. Fibroblast growth factor-2 (FGF-2) signalling promotes proliferation in both the SVZ and SGZ [37-39]. FGF-2 and TGF synthesis and secretion can be augmented by ATP, which can increase proliferation, and provide a potential explanation for the reduced neurogenesis in purinergic receptor knockout mice (P2Y1) [40, 41]. Other factors also play a role in neurogenesis, including neuregulin-1, which has been implicated in dentate gyrus neurogenesis in addition to having antidepressant effects [42] and Growth Hormone (GH) which augments EGF and FGF2-induced proliferation [43]. Growth factor signalling often leads to activation of Akt through phosphoinositide-3 kinase (PI-3K); one negative regulator of this pathway is the phosphatase and tumour suppressor PTEN, which has a role in regulating neurogenesis as demonstrated by increased proliferation and differ‐ entiation in mutant mice [44]. Furthermore, IGF-2 also regulates proliferation in the dentate gyrus in an Akt-dependent manner [45].

The gp130-associated cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), activate Janus kinase (JAK/signal transducer of transcription 3 (STAT3)), mito‐ gen activated protein (MAP) kinase and PI-3K/Akt pathways following ligand binding. These cytokines have been shown to regulate NSC proliferation and differentiation [46-49]. Specifically in the dentate gyrus, the activation of STAT3 from CNTF appears to be essential for the formation and maintenance of the NSCs [50]. The role of the JAK/STAT pathway will be discussed in more detail later. The MAPK pathway is important for neurogenesis as dem‐ onstrated by conditional knockdown of extracellular signal-related kinase 5 (ERK5) which limits neuronal differentiation and neurogenesis resulting in impaired contextual fear ex‐ tinction and remote fear memory [51, 52].

Other molecules shown to have a role in controlling neuronal differentiation include Prese‐ nilin-1 (PS1), which is the catalytic core of the aspartyl protease gamma-secretase. Reduction of PS1 enhances differentiation, primarily through its transducers the EGF receptor and βcatenin [53]. Interferon-γ, which signals via STAT1, and interferon-β which does not, both inhibit cultured adult NPC proliferation, but only interferon-γ promotes neuronal differen‐ tiation [54, 55].

the number and survival of NSCs in the SVZ and olfactory bulb [78-80]. Similarly, knock‐ down of TrkB receptors and disruption of BDNF signalling in dentate gyrus progenitors leads to shorter dendrites and reduced spine formation, culminating in a lack of survival [81]. Fibroblast growth factor (FGF-2) has a role in neurogenesis and memory consolidation

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related

Signalling Pathways

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http://dx.doi.org/10.5772/53268

Intrinsic factors are also necessary for the maturation and survival of newly born neurons. In the dentate gyrus, *Prox1* [18], *NeuroD* [82, 83] and Kruppel-like factor 9 [84] play impor‐ tant roles in survival. In the SVZ, *Pax6* and *Dlx-2* influence neuronal fate, leading to the pro‐ duction of dopaminergic periglomerular cells in the olfactory bulb [85-87]. New neurons in the dentate gyrus rely on cyclic response element binding protein (CREB) signalling for ma‐ turation and integration into the network. Interestingly, CREB activates miR-132 which reg‐ ulates dendrite maturation in newborn dentate gyrus granular neurons [88]. The collapsin response mediator protein-5 (CRMP5) is expressed in both the SVZ and dentate gyrus and CRMP5-/- mice show an increase in proliferation and neurogenesis in addition to displaying an increase in apoptosis of granular cells in both the olfactory bulb and dentate gyrus [89].

**4. Signalling cascades regulating NPC fate following neural damage**

Neurogenesis and gliogenesis are known to be initiated following brain damage, such as is‐ chemia, seizures, traumatic injury and neurodegenerative diseases [90-92]. However, these new neurons and glia usually do not effectively replenish those that were lost. Many of the normal signalling cascades are altered following injury. Below is a discussion of the major changes in these cascades that influence neuronal fate of the NSCs generated in the SVZ and

A traumatic lesion to the brain cortex results in an increase in proliferation of NSCs in the SVZ, although varied locations and degrees of injury have resulted in an incongruity of re‐ sults across the literature [93-98]. Nonetheless, it is generally agreed that the increase in pro‐ liferation results in an increase in neurogenesis at the SVZ [99]. Expression of growth factors such as BDNF, FGF2, GDNF, IGF-1 and VEGF are increased following ischemia and exoge‐ nous application further augments NSC proliferation and survival [100-105]. Shh expression is also upregulated in the SVZ following ischemia, potentially playing a role in the increase of proliferation, while Wnt expression does not change [106, 107]. Phosphorylated CREB is

Following proliferation these cells must migrate and integrate to damaged cortical tissue. The majority of research on ectopic migration from the SVZ has been performed following an ischemic insult and has demonstrated that cells do reach the injured striatum [90, 109-114]. It appears that the cells no longer migrate in a chain formation and carry on indi‐ vidually, interestingly, at the expense of the RMS population [109, 115]. This change in mi‐ gration is the direct result of chemoattractive cues expressed from the injury site.

upregulated following ischemia and induces hippocampal neurogenesis [108].

in this context [39].

SGZ following injury or disease.

**4.1. Brain injury**

#### **3.2. Migration and integration**

Migration from the SVZ along the RMS involves long distances and multiple pathways [56] For example, it is dependent on Shh signalling, as evident by a decrease of neuroblasts in the olfactory bulb following Hedgehog signalling interruption [11]. Shh is a chemoattractant cue extrinsic to the neuroblast that guides migration to the olfactory bulb. Neurotrophic growth factor signalling is also important for migration, in particular insulin-like growth factor (IGF-1) null mice show an abundance of neuroblasts in the SVZ that have failed to mi‐ grate to the olfactory bulb [57]. Guidance cues from EphB2/ephrin-B2 pathways also enable formation of the chain migration from the SVZ to the olfactory bulb [58]. Recently, endocan‐ nabinoid signalling has been shown to regulate migration and neurogenesis in both the SVZ and dentate gyrus [59, 60]. Other molecules involved in this migration include polysialated neural cell adhesion molecule (PSA-NCAM) [61-63], Slit-Robo [64] and integrins [65, 66]. Many of these factors signal via the Rho kinase pathway, which is a downstream regulator of NPC migration [67]. In addition adult NPCs express a range of chemokine receptors and chemokines are expressed in different brain regions, with the highest levels in the olfactory bulb, suggesting an as yet largely unexplored role for chemokines in regulating basal adult NPC migration [68].

The migration distance for new neurons from the SGZ is relatively short as they travel into the granular layer above the SGZ, where guidance molecules may control this movement. NMDA receptor signalling is required for the proper migration of newborn granular cells in the dentate gyrus [69]. This is achieved through the activation of Disrupted-in-schizophre‐ nia (DISC1), as neurons without DISC1 migrate further into granular layer and into the mo‐ lecular layer [69, 70]. DISC1 also controls the dendritic maturation of newborn granule cells through GABA depolarization of NKCC1 and activation of the Akt-mTOR pathway [70, 71].

New neurons must integrate into existing circuitry or they will not survive. The vast majority of new neurons do not survive past 4 weeks. Interestingly, NMDA receptors expressed in neu‐ roblasts along the RMS are crucial to the integration of these neurons in existing olfactory bulb circuitry [72]. Glutamate is released from astrocyte-like cells that surround the neuroblasts. NMDA receptor activation in newly-born dentate gyrus granule cells also increases survival. Initial GABA depolarization plays a role in the maturation of neurons in the dentate gyrus and olfactory bulb [73, 74]. This depolarization and subsequent Ca2+ influx are required for den‐ drite initiation and elongation [75]. This process involves coordinated expression of the GABA receptor subunit alpha2 that controls the maturation of the new neurons [76]. In addition, ag‐ rin signalling is necessary for integration and survival of newborn neurons in the olfactory bulb, as demonstrated by a loss of agrin leading to improper synapse formation while an over‐ expression of agrin results in an increase in dendritic spines [77].

Neurotrophin signalling has important role in the survival and integration of new neurons. Brain-derived growth factor (BDNF) binding to the TrkB receptor tyrosine kinases increases the number and survival of NSCs in the SVZ and olfactory bulb [78-80]. Similarly, knock‐ down of TrkB receptors and disruption of BDNF signalling in dentate gyrus progenitors leads to shorter dendrites and reduced spine formation, culminating in a lack of survival [81]. Fibroblast growth factor (FGF-2) has a role in neurogenesis and memory consolidation in this context [39].

Intrinsic factors are also necessary for the maturation and survival of newly born neurons. In the dentate gyrus, *Prox1* [18], *NeuroD* [82, 83] and Kruppel-like factor 9 [84] play impor‐ tant roles in survival. In the SVZ, *Pax6* and *Dlx-2* influence neuronal fate, leading to the pro‐ duction of dopaminergic periglomerular cells in the olfactory bulb [85-87]. New neurons in the dentate gyrus rely on cyclic response element binding protein (CREB) signalling for ma‐ turation and integration into the network. Interestingly, CREB activates miR-132 which reg‐ ulates dendrite maturation in newborn dentate gyrus granular neurons [88]. The collapsin response mediator protein-5 (CRMP5) is expressed in both the SVZ and dentate gyrus and CRMP5-/- mice show an increase in proliferation and neurogenesis in addition to displaying an increase in apoptosis of granular cells in both the olfactory bulb and dentate gyrus [89].
