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provided by Frontiers - Publisher Connector REVIEW ARTICLE published: 26 June 2013 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2013.00100 Wnt signaling in the regulation of adult hippocampal

Lorena Varela-Nallar 1* and Nibaldo C. Inestrosa 2

1 Centro de Investigaciones Biomédicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile 2 Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

Edited by: In the adult brain new are continuously generated mainly in two regions, the Juan P. Henríquez, Universidad de (SVZ) of the and the (SGZ) in Concepción, Chile the hippocampal . In the SGZ, radial neural stem cells (NSCs) give rise to Reviewed by: granule cells that integrate into the hippocampal circuitry and are relevant for the plasticity Francisco J. Nualart, Universidad de Concepción, Chile of the . Loss of neurogenesis impairs and , suggesting Manuel Cifuentes, Universidad de that this process is important for adult hippocampal function. Adult neurogenesis is Málaga, Spain tightly regulated by multiple signaling pathways, including the canonical Wnt/β-catenin *Correspondence: pathway. This pathway plays important roles during the development of neuronal circuits Lorena Varela-Nallar, Centro de and in the adult brain it modulates synaptic transmission and plasticity. Here, we Investigaciones Biomédicas, Facultad de Ciencias Biológicas y review current knowledge on the regulation of adult hippocampal neurogenesis by the Facultad de Medicina, Universidad Wnt/β-catenin signaling cascade and the potential mechanisms involved in this regulation. Andrés Bello, República 239, Also we discuss the evidence supporting that the canonical Wnt pathway is part of the Santiago 8370146, Chile signaling mechanisms involved in the regulation of neurogenesis in different physiological e-mail: [email protected] conditions. Finally, some unsolved questions regarding the Wnt-mediated regulation of neurogenesis are discussed.

Keywords: neurogenesis, hippocampus, adult hippocampal progenitor (AHP), subgranular zone (SGZ), , β-catenin

INTRODUCTION 2001; Kempermann et al., 2004). These progenitors (type 1 cells) The adult brain is able to continuously generate new neurons, that are slowly dividing or quiescent, also express and the a process known as neurogenesis, which has been reported in factor . A morphologically distinct class of a number of mammalian species. Adult neurogenesis occurs type 1 cells that has horizontal processes has also been identified mainly in two specific brain regions, the subventricular zone (Lugert et al., 2010). The horizontal and radial progenitors have (SVZ) of the lateral ventricles and the subgranular zone (SGZ) different proliferation rate and respond differently to neurogenic in the hippocampal dentate gyrus (Alvarez-Buylla and Garcia- stimuli (Suh et al., 2007; Lugert et al., 2010), suggesting that Verdugo, 2002; Zhao et al., 2008)(Figure 1A). Through intrinsic in the SGZ there are different populations of progenitors with and extrinsic factors adult neurogenesis is tightly regulated to different properties, increasing the complexity of the cellular allow the maintenance and self-renewal of the stem pool and and molecular mechanisms underlying regulation of adult the generation of fully functional neurons. Here, we review the neurogenesis. Intrinsic properties of NSCs present in the SGZ, findings specifically supporting the role of the Wnt pathway in such as self-renewing and multipotency, are still a matter of the adult hippocampal neurogenesis, and also discuss different debate (Bonaguidi et al., 2011; Encinas et al., 2011; Ming and studies indicating that this pathway is part of the signaling mech- Song, 2011). These cells can be isolated and cultured generating anisms involved in the regulation of neurogenesis by different self-renewing cells that can differentiate into neurons (Palmer physiological conditions. et al., 1997; Peltier et al., 2010). Adult neurogenesis is a multistep process. In the SVZ When activated, type 1 cells give rise to fast proliferating type -like neural stem cells (NSCs), called type B1 cells, 2 cells or transit-amplifying progenitors that express nestin and generate type C cells that rapidly proliferate and give rise to Sox2 but not GFAP (Kempermann et al., 2004). After limited type A (Figure 1B). These cells migrate through the number of cell divisions, type 2 cells commit to the neuronal to the where they became lineage generating type 3 cells or neuroblasts which are prolifera- (Alvarez-Buylla and Garcia-Verdugo, 2002). In the tive and express (DCX) but not nestin (Kronenberg SGZ, NSCs that give rise to granule cells are present at the border et al., 2003). Neuroblasts then became immature neurons that between the hilus and the layer (Gage, 2000). Glial extend dendrites toward the molecular layer and project their fibrillary acidic (GFAP)-expressing radial -like cells, through the hilus toward the CA3 region (Figure 1C), which extend a single radial process toward the molecular layer and during several weeks mature into functional dentate gran- (Figure 1C),areproposedtobethestemcellsorundifferentiated ule neurons that are integrated into the pre-existing hippocampal precursors that generate dentate granule neurons (Seri et al., circuitry and are located mainly in the inner granular cell layer

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FIGURE 1 | Neurogenic niches in the adult brain. (A) Schematic neuroblasts, which migrate through the rostral migratory stream (RMS) representation of the neurogenic regions in the adult brain: the to the olfactory bulb (OB) where they mature into interneurons. (C) subgranular zone (SGZ) in dentate gyrus (DG) of the hippocampus, Neurogenesis in the SGZ. Radial type 1 cells give rise to type 2 cells and the subventricular zone (SVZ) in the later wall of the lateral that differentiate into type 3 neuroblasts that become immature ventricles. (B) SVZ niche composed of type B1 cells, that corresponds neurons and then mature into granule neurons that migrate into the to neural stem cells, type C cells that rapidly proliferate and type A granule cell layer. of the dentate gyrus (Van Praag et al., 2002; Zhao et al., 2006; hippocampal neurogenesis including Wnt, Notch, sonic hedge- Mathews et al., 2010). Thus, neurogenesis can be divided into hog (Shh), bone morphogenetic (BMP), growth and sequential stages: activation of quiescent stem cells, prolifera- neurotrophic factors and neurotransmitters (Suh et al., 2009; tion, neuronal fate specification, maturation and integration of Schwarz et al., 2012; Faigle and Song, 2013). Also, there is a fine newborn neurons. tuned transcriptional control involving a number of transcrip- For the continuous generation of new neurons in the adult tional factors and epigenetic mechanisms that will coordinate brain there should be a tight regulation of the sequential steps the progression of neurogenesis (Ming and Song, 2011; Hsieh, of neurogenesis. Intrinsic factors should coordinate the proper 2012; Schwarz et al., 2012). In addition, the rate of prolifera- progression of neurogenesis and preserve the pool. tion, differentiation, and survival of newborn neurons in the An impaired maintenance of the quiescent pool may result in hippocampus can be modulated by different physiological stimuli an excessive proliferation and differentiation and ultimately in such as hippocampal-dependent learning and neuronal activity, the depletion of precursor cells. If commitment and differenti- exposure to (EE), running and ation of precursor cells into neurons is disturbed, there could (Kempermann et al., 1997; Gould et al., 1998; Van Praag et al., be no generation of new neurons even in the presence of the 1999; Dobrossy et al., 2003; Drapeau et al., 2007; Piatti et al., 2011; stem cells pool. Therefore, there should be a balance between Song et al., 2012). the self-renewal and maintenance of stem cells and the dif- Increasing evidence indicate that adult neurogenesis is impor- ferentiation into neurons. Several signaling molecules regulate tant for hippocampal function, being relevant for the plasticity

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of the hippocampal network (Snyder et al., 2001; Mongiat and (Lie et al., 2005; Adachi et al., 2007; Toledo et al., 2008; Kuwabara Schinder, 2011). Newborn neurons impact the hippocampal cir- et al., 2009; Inestrosa and Arenas, 2010). Consistent with the pre- cuitry mainly while still immature, when these cells have distinct vious feature, in the adult brain most of the key components of functional properties showing increased excitability and reduced the Wnt signaling including Wnts and Fz receptors are expressed GABAergic inhibition (Wang et al., 2000; Schmidt-Hieber et al., (Shimogori et al., 2004; Chen et al., 2006; Chacon et al., 2008). 2004; Esposito et al., 2005; Ge et al., 2007; Marin-Burgin et al., Different studies have shown that the Wnt/β-catenin pathway 2012). Loss of neurogenesis impairs learning and memory indi- is involved in adult hippocampal neurogenesis. In the BAT-gal cating that this process has functional implications for the adult reporter mouse expressing a β-catenin-activated transgene with brain (Reviewed in Deng et al., 2010; Koehl and Abrous, 2011; nuclear β-galactosidase under the control of TCF/Lef (Maretto Marin-Burgin and Schinder, 2012). et al., 2003), it was determined that the Wnt/β-catenin pathway is active in the SGZ and the dentate granule cell layer in the THE Wnt/β-CATENIN SIGNALING PATHWAY IN THE adult hippocampus (Lie et al., 2005). In addition, cultured adult REGULATION OF ADULT HIPPOCAMPAL NEUROGENESIS hippocampal progenitors (AHPs) express key components of the Wnts compromise a large family of secreted glycoproteins that Wnt/β-catenin signaling pathway including some Fz receptors are part of the signaling molecules regulating several aspects of (Lie et al., 2005; Wexler et al., 2009). Adult hippocampal astro- development such as axis formation and midbrain development cytes express Wnt-3, and it was shown that Wnts derived from (Van Amerongen and Nusse, 2009; Nusse and Varmus, 2012). The hippocampal stimulate Wnt/β-catenin signaling in iso- interaction of a Wnt protein with members of the Frizzled (Fz) lated AHPs and induce the differentiation of these progenitors family of seven-pass transmembrane cell-surface receptors trig- into neurons, since the differentiation induced by co-culture with gers the activation of the Wnt signaling pathway (Gordon and astrocytes was reduced in the presence of the Wnt inhibitor sol- Nusse, 2006; Wang et al., 2006; Schulte, 2010). In mammals 19 uble Frizzled-related protein 2 and 3 (sFRP2/3) (Lie et al., 2005). Wnt members have been found and 10 members of the Fz fam- In addition to astrocytes-derived Wnts, there is an autocrine Wnt ily have been identified. In addition, receptor-like tyrosine kinase signaling activity in AHPs (Wexler et al., 2009). Interestingly, inhi- (Ryk) and receptor tyrosine kinase-like orphan receptor (Ror2) bition of the autocrine Wnt stimulation increases the number have been identified as alternative Wnt receptors (Oishi et al., of neurons formed and depletes multipotent progenitors indi- 2003; Keeble et al., 2006; Ho et al., 2012). Downstream Wnt cating that this autocrine pathway supports the proliferation and receptors, different Wnt signaling cascades may be activated: the multipotency of stem cells and therefore, it may preserve the bal- Wnt/β-catenin or canonical pathway that involves gene transcrip- ance between NSC maintenance and differentiation (Wexler et al., tion, and the β-catenin-independent or non-canonical pathways 2009). Therefore, Wnts are important for both, the maintenance that induce either an increase in intracellular calcium concentra- of the stem cell pool and the differentiation of newborn neurons. tion or activation of the c-Jun-N-terminal kinase (JNK) cascade Regulation of adult neurogenesis by Wnt signaling was also (Veeman et al., 2003; Gordon and Nusse, 2006; Angers and Moon, demonstrated in vivo by stereotactic injection of lentiviral vectors 2009). expressing Wnt-3 or a secreted mutant Wnt-1 protein that blocks In the canonical Wnt/β-catenin signaling low-density lipopro- the Wnt signaling (Lie et al., 2005). Wnt signaling inhibition tein receptor-related proteins 5 and 6 (LRP5/6) serve as co- reduced proliferation and neurogenesis in the SGZ, while activa- receptors for Wnt ligands. Activation of the canonical signaling tion of the Wnt signaling increased neurogenesis (Lie et al., 2005). pathway activates the protein Dishevelled (Dvl) by phosphoryla- Later on, and by using the same lentiviral approach to block tion, and triggers the stabilization of cytoplasmic β-catenin, that Wnt signaling activation in the dentate gyrus of adult rats, it was in the absence of Wnt stimulation is ubiquitinated and constantly shown that reduction of neurogenesis by Wnt inhibition impaired degraded in the proteasome (Aberle et al., 1997). β-catenin enters long-term retention of and object recognition the nucleus and binds to members of the family of T-cell fac- memory, indicating that Wnt-mediated adult hippocampal neu- tor (TCF) and lymphoid enhancer factor (Lef) and this binding rogenesis contributes to hippocampal function (Jessberger et al., activates transcription by displacing the repression of Wnt target 2009). genes (Nusse and Varmus, 2012). The importance of the Wnt pathway in neurogenesis is also During development, Wnt signaling is fundamental for the supported by studies focusing on the role of a key component proper development of cortex and hippocampus (Li and Pleasure, of the Wnt/β-catenin pathway, the enzyme glycogen synthase 2005; Machon et al., 2007). Wnt signaling promotes self-renewal kinase-3β (GSK-3β). In the absence of Wnt stimulation, β-catenin of cortical neural progenitors and the differentiation of these is phosphorylated by GSK-3β in a multiprotein complex com- progenitors in a stage specific manner (Hirabayashi et al., 2004; posed also of the scaffold protein axin and adenomatous poly- Munji et al., 2011). During early neurogenesis the Wnt pathway posis coli (APC) (Hart et al., 1998; Ikeda et al., 1998; Itoh et al., promotes self-renewal and maintains neural progenitors (Chenn 1998; Kishida et al., 1998; Sakanaka et al., 1998). Phosphorylated and Walsh, 2002; Machon et al., 2007; Wrobel et al., 2007), while β-catenin is recognized by β-TrCP, which is part of an E3 ubiqui- it induces the differentiation of intermediate progenitors during tin ligase complex, is ubiquitinated and subsequently degraded mid and late neurogenesis (Munji et al., 2011). In addition to the (Liu et al., 2002). Activation of the Wnt/β-catenin pathway key roles of the Wnt pathway during development, it has proved inhibits the degradation pathway and induces the cytoplasmic to be important in the adult brain, where it regulates stabilization of β-catenin and the transcription of Wnt target formation, neurotransmission and plasticity, and neurogenesis genes (Logan and Nusse, 2004). In vitro experiments show that

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treatment with the GSK-3β inhibitor lithium induces the prolifer- This study also revealed that Wnt-7a is important for adult NSC ation of AHPs (Wexler et al., 2008). In vivo treatment with lithium proliferation in vivo, since a decreased proliferation was observed was also shown to stimulate proliferation and neuronal fate speci- in the SGZ and SVZ of adult Wnt-7a knockout mice. In TLX−/− fication in a mouse model of Alzheimer’s disease (Fiorentini et al., mice, intracranial lentiviral transduction of active β-catenin led 2010). Besides, a decreased neurogenesis was observed in a GSK-3 to a considerable rescue of cell proliferation in the SVZ, suggest- knock-in mouse carrying mutations to block inhibitory phos- ing that Wnt/β-catenin acts downstream of TLX to regulate NSC phorylation of the kinase (Eom and Jope, 2009). In this model, proliferation in vivo (Qu et al., 2010). it was suggested that the impaired neurogenesis was not con- Although it is out of the scope of the present review, it sequence of the effects of GSK-3 in neural progenitor cells but is important to mention that other studies have demonstrated rather by alterations in the external support for the proliferation that neurogenesis in the SVZ is also Wnt-regulated. Retrovirus- of these cells. GSK-3β has also been involved in the disrupted in mediated expression of a stabilized β-catenin in vivo promoted 1 (DISC1)-mediated regulation of adult neurogen- the proliferation of type C cells and inhibited their differentiation esis. DISC-1 is a schizophrenia susceptibility gene that regulates into neuroblasts (Adachi et al., 2007). Also in the SVZ, trans- multiple steps of neurogenesis (Duan et al., 2007; Mao et al., duction of the β-catenin inhibitor axin by intracranial lentiviral 2009). Interestingly, DISC1 protein inhibits GSK-3β activity, and delivery decreased cell proliferation (Qu et al., 2010), further sup- it is required for Wnt-3a-induced proliferation of cultured AHP porting a role for Wnt/β-catenin signaling in NSC proliferation in cells and β-catenin-dependent transcription (Mao et al., 2009). the neurogenic areas of the adult brain. The impairment in proliferation caused by DISC1 Although the Wnt/β-catenin pathway is required for different knockdown could be rescued by over expression of stabilized β- aspects of adult hippocampal neurogenesis, excessive β-catenin catenin. In vivo, cell proliferation in the adult dentate gyrus could signaling may impair the maturation of adult born neurons. It be rescued by administration of a GSK-3β inhibitor, which also was determined that the impaired dendritic refinement in adult suppressed schizophrenia- and -like behaviors caused born dentate granule cells observed by primary cilia loss is a by DISC1 loss of function (Mao et al., 2009). These findings link consequence of an abnormal enhancement of β-catenin signal- the DISC1-mediated regulation of neurogenesis with downstream ing in newborn neurons as conditional knockout of β-catenin components of the Wnt/β-catenin signaling pathway. reversed the decrease observed in the total dendritic length Recently, a negative effect on neurogenesis was determined for in these neurons (Kumamoto et al., 2012). Moreover, expres- two Wnt inhibitors, Dickkopf 1 (Dkk1) and sFRP3 (Jang et al., sion of a constitutively active β-catenin suppresses the dendritic 2013; Seib et al., 2013). Dkk1 binds LRP co-receptors preventing refinement of newborn neurons between 14 and 21 after born the formation of the Fz/LRP complex and the consequent acti- (Kumamoto et al., 2012). Therefore, impaired Wnt/β-catenin sig- vation of the Wnt signaling cascade (Clevers and Nusse, 2012); naling after migration of newborn neurons may have detrimental sFRPs bind to Wnts preventing its interaction with cellular recep- consequences, suggesting that there should be a fine tuned acti- tors and the activation of the Wnt pathway (Rattner et al., 1997). vation of β-catenin signaling to allow for proper maturation and Inducible deletion of Dkk1 in the adult CNS resulted in an integration of newborn neurons. increased self-renewal of neural progenitors and increased gen- eration of immature neurons (Seib et al., 2013). On the other Wnt/β-CATENIN PATHWAY AS PART OF THE SIGNALING hand, sFRP3 knockdown in the dentate gyrus through a lentiviral MECHANISMS INVOLVED IN THE REGULATION OF approach increased Wnt signaling and increased neural progeni- NEUROGENESIS IN DIFFERENT PHYSIOLOGICAL tor proliferation (Jang et al., 2013). Interestingly, deletion of Dkk1 CONDITIONS and sFRP3 knockdown resulted in an increased dendrite com- In addition to the discussed evidence directly pointing to the plexity of immature neurons indicating that Wnt signaling is involvement of the Wnt signaling pathway in the proliferation important for dendritic development of newborn neurons (Jang and differentiation of adult neural progenitor cells, studies have et al., 2013; Seib et al., 2013). The negative effect of both inhibitors indicated this pathway as part of the mechanisms involved in the on neurogenesis suggests that suppression of Wnt signaling by regulation of neurogenesis under some physiological conditions. secreted factors could be a regulatory mechanism to dynami- cally modulate neurogenesis under physiological and pathological AGING stimulation as we will discuss afterward. During lifespan there is a progressive reduction of hippocampal Also, the Wnt pathway is part of the signaling mechanisms neurogenesis that have been evidenced in different species (Kuhn of the orphan nuclear receptor TLX (also known as NR2E1), et al., 1996; Gould et al., 1999; Leuner et al., 2007; Olariu et al., an important regulator of NSC maintenance and self-renewal in 2007; Varela-Nallar et al., 2010b), including humans (Knoth et al., embryonic and adult brains (Shi et al., 2004; Li et al., 2008b) 2010). The generation of new neurons in the adult human den- that is required for adult neurogenesis in the SVZ (Liu et al., tate gyrus was originally evidenced in postmortem tissues from 2008)andSGZ(Zhang et al., 2008). It was determined that TLX patients who were treated with the analog bromod- activates the Wnt/β-catenin pathway in adult mouse NSC to stim- eoxyuridine (BrdU) (Eriksson et al., 1998). Thereafter, several ulate proliferation and self-renewal by activating the expression studies have suggested that neurogenesis in humans can be reg- of Wnt-7a through binding to the two TLX binding sites present ulated by different physiological and pathological conditions (Jin intheWnt-7agenepromoter(Qu et al., 2010). In accordance, et al., 2004; Li et al., 2008a; Gerber et al., 2009; Mattiesen et al., Wnt-7a expression was found down-regulated in TLX-null mice. 2009; Boldrini et al., 2012). As determined in other species, it was

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shown a reduction of DCX expressing cells with increasing age in response to global ischemia (Liu et al., 1998). Also, inter- suggesting that there is an age-related decline in the generation of mittent hypobaric hypoxia regimen promoted the proliferation new neurons in the human hippocampus (Knoth et al., 2010). of endogenous neural progenitors leading to more newborn In , evidence indicate that a decline in Wnt signal- neurons in the hippocampus of adult rats (Zhu et al., 2010). ing is associated to the age-dependent reduction in neurogene- Interestingly, there has been suggested an association between sis. During aging, the levels of Wnt-3 protein in hippocampal hypoxia and the Wnt/β-catenin pathway in embryonic stem cells astrocytes and also the number of Wnt-3-secreting astrocytes (ESCs) and NSCs. Hypoxia increases β-catenin signaling in ESCs decline (Okamoto et al., 2011). This finding is important since and increases the expression of Lef1 and TCF1 genes (Mazumdar as previously mentioned, Wnts derived from hippocampal astro- et al., 2010). The hypoxia-mediated activation of the Wnt path- cytes stimulate Wnt/β-catenin signaling in neural progenitors and way is mediated by hypoxia-inducible -1α induce its neural differentiation (Lie et al., 2005). It was shown (HIF-1α) that directly binds to the of the Lef1 and TCF1 in rats that there is a progressive decrease in the expression of genes in cultured ESC under hypoxic conditions (Mazumdar Wnt-3 and Wnt-3a in the dentate gyrus between 2 and 22 month, et al., 2010). Moreover, it was determined in the BAT-gal reporter concomitantly with a decrease in the expression of NeuroD1 mouse that the Wnt/β-catenin signaling is active in low oxygen (Okamoto et al., 2011). NeuroD1 is a basic helix-loop-helix tran- regions in the adult brain, including in the SGZ. This suggests an scription factor important for the generation of granule cells and association between low oxygen and β-catenin signaling in vivo, olfactory neurons in the embryonic and adult brain (Gao et al., which was shown to be dependent of HIF-1α (Mazumdar et al., 2009). This suggests that the decline in Wnt-3/Wnt-3a expression 2010). in astrocytes may cause the decreased expression of proneural genes and in consequence the decrease in neurogenesis. More POTENTIAL MECHANISMS INVOLVED IN THE recently, the Wnt inhibitor Dkk1 was also involved in the age- Wnt-MEDIATED REGULATION OF ADULT HIPPOCAMPAL related decline in neurogenesis (Seib et al., 2013). As mentioned, NEUROGENESIS Dkk1 is a suppressor of NSCs proliferation. The expression of How the Wnt/β-catenin signaling could regulate neurogenesis? Dkk1 increases with age, suggesting that suppression of Wnt sig- The molecular mechanism may involve the transcriptional activa- naling by this inhibitor may downregulate neurogenesis during tion of NeuroD1 which depends on the Wnt/β-catenin signaling aging (Seib et al., 2013). Whether Wnt is associated to the age- activation (Kuwabara et al., 2009). NeuroD1 gene promoter has related decline in neurogenesis in humans is not known, but it was overlapping DNA-binding site for Sox2 and TCF/Lef, then the reported an association between Wnt-3 levels and cell prolifera- activation of this gene implies activation of the canonical Wnt tion in the human hippocampus (Gerber et al., 2009), suggesting pathway and removal of Sox2 repression from the NeuroD1 gene that this pathway may also regulate neurogenesis in the human promoter (Kuwabara et al., 2009). Prox1 is also a Wnt target gene brain. that could be relevant for the neurogenic effect of the Wnt/β- catenin pathway (Karalay et al., 2011). Prox1 is expressed in newborn and mature granule cells and is required for the proper Running, which is one of the physiological stimuli that strongly differentiation and survival of newborn granule cells, but not for stimulates adult neurogenesis in the SGZ (Van Praag et al., 1999), the maintenance of granule cells after they have fully matured modulates the expression of genes involved in Wnt signaling (Karalay et al., 2011). Interestingly, the promoter region of long (Stranahan et al., 2010). Moreover, running was found to sig- interspersed element-1 (L1) retrotransposons, which was found nificantly increase the expression of Wnt-3 in astrocytes of the to be actively retrotransposed during neurogenesis (Muotri et al., dentate gyrus (Okamoto et al., 2011)andtoincreasethepopu- 2005; Coufal et al., 2009), contains dual binding sites for Sox2 and lation of Wnt-3 expressing cells in young and aged mice. More TCF/Lef (Kuwabara et al., 2009). Therefore, Wnt signaling activa- recently, it was shown that exercise also regulates the expres- tion could upregulate the expression of genes adjacent to the L1 sion of the Wnt inhibitor sFRP3, which is a suppressor of adult loci that may be relevant for neurogenesis such as DCX (Okamoto hippocampal neurogenesis (Jang et al., 2013). Exercise as well et al., 2011). as electroconvulsive stimulation (ECS) decreased the expression In addition, the Wnt signaling pathway could directly or of sFRP3 in dentate granule neurons, and infusion of sFRP3 indirectly modulate neurogenesis through the regulation of glu- into the dentate gyrus abolished the ECS-induced increase of tamatergic neurotransmission in the hippocampus, since neural neural progenitor proliferation (Jang et al., 2013), suggesting progenitor cells respond to neuronal activity as part of their dif- that the reduction of sFRP3 levels is important for the activity- ferentiation program (Deisseroth et al., 2004). We and others have mediated increase in neurogenesis. In addition to the reported determined that Wnt ligands regulate synaptic assembly as well increase of Wnt-3 levels by running, this finding strongly impli- as and neurotransmission in the hippocampus. cates the Wnt pathway as a signaling mechanisms involved in the In cultured hippocampal neurons, Wnt-3a, Wnt-7a and Wnt-7b excercise-mediated increase in neurogenesis. regulate pre-synaptic assembly increasing the number of pre- synaptic puncta (Ahmad-Annuar et al., 2006; Cerpa et al., 2008; HYPOXIA Davis et al., 2008). In addition, Wnt-7a stimulates the clustering An association between hypoxia and neurogenesis in embry- of the pre-synaptic receptor α7- nicotinic acetylcholine receptor onic and adult brain has been demonstrated by different studies. (Farias et al., 2007), indicating that the Wnt signaling regulates Increased neurogenesis in the rodent dentate gyrus was observed the clustering of pre-synaptic receptors. Evidence indicate that

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these ligands are able to modulate pre-synaptic differentiation study whether this pathway regulates the proper polarization and by activation of the Wnt/β-catenin signaling pathway. In accor- migration of newborn neurons in the adult brain as it does during dance with the structural data, electrophysiological recordings development. On the other hand, the activation of the Wnt/Ca2+ have revealed that Wnts have modulatory effects on glutamater- pathway triggers the increase in intracellular Ca2+ levels and acti- gic neurotransmission (Ahmad-Annuar et al., 2006; Cerpa et al., vates the protein kinases CamKII and protein kinase C (PKC) 2008; Varela-Nallar et al., 2010a; Avila et al., 2010). On adult rat (Veeman et al., 2003; Kohn and Moon, 2005). hippocampal slices, Wnt-7a increases neurotransmitter release in We have determined that non-canonical Wnt pathways have CA3-CA1 increasing the frequency of miniature excitatory post- relevant roles in the adult hippocampus. In cultured hip- synaptic currents (mEPSC) (Cerpa et al., 2008). Wnt-3a is also pocampal neurons, the Wnt-5a ligand able to activate non- able to increase the frequency of mEPSC in cultured hippocam- canonical Wnts cascades (Farias et al., 2009; Cuitino et al., pal neurons (Avila et al., 2010). The synaptic effects of Wnts could 2010), plays relevant roles in synaptic structure and func- regulate the generation and maturation of newborn neurons. tion. Wnt-5a increases dendritic spine morphogenesis (Varela- Importantly, the release and expression of Wnt ligands is mod- Nallar et al., 2010a), effect also described for Wnt-7a which ulated by neuronal activity (Chen et al., 2006; Wayman et al., increase the density and maturity of dendritic spines through 2006; Tabatadze et al., 2012), and incubation of adult hippocam- a non-canonical CamKII-dependent mechanism (Ciani et al., pal slices with secreted Wnt inhibitors affects glutamatergic neu- 2011). In addition, Wnt-5a increases the clustering of the rotransmission (Chen et al., 2006; Varela-Nallar et al., 2010a; post-synaptic density protein-95 (PSD-95) (Farias et al., 2009). Cerpa et al., 2011), strongly suggesting that endogenous Wnt sig- PSD-95 is a scaffold protein of the post-synaptic density, a naling in the brain modulates hippocampal function and could multiprotein complex containing key molecules involved in modulate the generation of new neurons. the regulation of glutamate receptor targeting and traffick- The in vivo relevance of the Wnt signaling in the hippocam- ing and regulatory proteins relevant for neurotransmission (Li pal function is demonstrated by the effects of EE, which increases and Sheng, 2003; Han and Kim, 2008). Electrophysiological Wnt-7a/b levels in CA3 pyramidal neurons in parallel to increas- data supports the synaptic roles of Wnt-5a. Acute application ing the complexity and number of large mossy fiber terminals of Wnt-5a increases the amplitude of field excitatory post- in the CA3 region (Gogolla et al., 2009). Interestingly, inhibit- synaptic potentials (fEPSP) in hippocampal slices (Varela-Nallar ing Wnt signaling through local application of the Wnt inhibitor et al., 2010a) and upregulates synaptic NMDA receptor cur- sFRP-1 suppressed EE effects. Also, it was determined that train- rents facilitating induction of long-term potentiation (LTP) ing in the hidden platform Morris water maze task increases the (Cerpa et al., 2011). Non-canonical ligands could indirectly influ- levels of Wnt-7a/b in granule cells of rat dentate gyrus but not ence the proliferation and differentiation of progenitor cells in CA3 pyramidal cells (Tabatadze et al., 2012). The increase through modulating hippocampal neurotransmission, or could of hippocampal Wnt-7a/b levels was still observed 30 days after directly regulate synaptogenesis and connectivity of newborn training, indicating that this is a long-lasting effect that could neurons. be associated to long-term spatial memory (Tabatadze et al., Wnt-5a also induces the recycling of functional GABAA recep- 2012). Therefore, Wnt signaling pathway is regulated by neuronal tors on hippocampal neurons through activation of CaMKII, and activity and regulates neurotransmission. The activity-mediated modulates inhibitory (Cuitino et al., 2010). GABA is Wnt signaling activation could modulate adult hippocampal neu- critical for the proper development and maturation of adult-born rogenesis which may contribute to Wnt-mediated increase in neurons (Tozuka et al., 2005; Ge et al., 2006; Jagasia et al., 2009), hippocampal plasticity. therefore the effect of this ligand on the inhibitory synapse may influence the development of newborn neurons. UNSOLVED QUESTIONS AND FUTURE PERSPECTIVES Interestingly, it was determined that training in the hidden Although the evidences indicate that Wnts are part of the signal- platform Morris water maze task increased hippocampal Wnt-5a ing molecules that regulate neurogenesis in physiological condi- levels (Tabatadze et al., 2012), suggesting that this ligand is also tions, there are still unsolved questions remaining. In this part regulated by activity and may regulate neurogenesis under certain we will discuss two attractive issues that from our point of view stimuli. should be addressed in the future. The effect of Wnt-5a was addressed in postnatal SVZ (Pino et al., 2011). In neural precursor cells cultured from the SVZ PUTATIVE ROLE OF THE NON-CANONICAL Wnt SIGNALING CASCADES of mice at postnatal day 5, Wnt-5a treatment increased neu- IN ADULT HIPPOCAMPAL NEUROGENESIS rite outgrowth, effect completely different to Wnt-3a treatment One aspect that should be addressed is the potential role of that inhibited neurite development (Pino et al., 2011), suggesting non-canonical Wnt signaling cascades. There are at least two that non-canonical pathway increases neurite complexity while β-catenin-independent pathways: the planar cell polarity (PCP) canonical pathway suppresses dendrite maturation. Whether the pathway and the Ca2+ pathway. The PCP pathway, also known same regulation takes place in the SGZ is not known. as the Wnt/JNK pathway, was originally identified in Drosophila where it regulates tissue polarity and cell migration (Adler, 2002; Wnt RECEPTOR CONTEXT COULD SPECIFICALLY REGULATE THE Veeman et al., 2003). This signaling pathway activates small DIFFERENT STAGES OF NEUROGENESIS GTPases including Rho and Rac and the protein kinase JNK, Considering that different populations of stem and progenitor and affects cytoskeleton dynamics. It would be interesting to cells have been identified in the SGZ, with different proliferation

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rates and response to neurogenic stimuli, it should be interest- in the structural organization of neurotransmitter release sites ing to evaluate whether these populations have different ability to that is recruited early during synapse formation (Zhai et al., respond to the signaling molecules present in the local microenvi- 2000). As well, Fz5 which is also present in synaptosomes and ronment. Progenitor cells, as well as newborn neurons at different co-localizes with synaptic markers, modulates the synaptogenic stages of maturity, may have different subsets of receptors and/or effect of Wnt-7a (Sahores et al., 2010). Changes in the expression co-receptors for the Wnt signaling pathway, which may mimic of this receptor modulates the density of synaptic sites in mature what is observed in hippocampal neurons (Varela-Nallar et al., neurons (Sahores et al., 2010). 2012). The expression pattern of Fz receptors during postna- The effects of Wnts on the proliferation of progenitor tal development is very different, being some of them highly cells and neuronal differentiation could be mediated by selec- expressed in adulthood and others during early postnatal devel- tive Wnt/receptor complexes. As mentioned, there are 19 Wnt opment. In cultured hippocampal neurons, the distribution of members, 10 Fz receptors and alternative receptors and co- Fzs is also very specific being some of them located in synap- receptors described in mammals, therefore there is a complex tic regions and others in the soma or growth cones of young scenario in which there is a wide range of possible inter- neurons (Varela-Nallar et al., 2012). Interestingly, the distribu- actions that may specifically regulate all aspects of neuro- tion of Fz receptors seems to be associated to specific functions. genesis. In this context, Wnt ligands constitutively expressed Fz1 that is located in the synaptic region co-localizing with pre- in the hippocampus may induce different signaling cascades synaptic proteins and with active synaptic vesicle recycling sites in stem cells, progenitors and newborn neurons by interact- (Varela-Nallar et al., 2009), regulates pre-synaptic differentiation. ing with specific sets of receptors and co-receptors, and in Overexpression of Fz1 receptor increased the clustering of the that way may regulate the sequential events of neurogenesis active zone protein Bassoon (Varela-Nallar et al., 2009), involved (Figure 2).

FIGURE 2 | Specific Wnt receptors could regulate the progression of the dentate gyrus. Wnt ligands constitutively expressed in the neurogenesis in the hippocampus. Schematic illustration of hippocampus could induce different signaling cascades in these cells and neurogenesis in the SGZ. As represented, stem cells, progenitor cells, regulate different stages of neurogenesis by interacting with specific immature and mature granule neurons are constantly present in receptors (see text for details).

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The receptor context may also be essential for specific effects CONCLUSIONS of canonical and non-canonical Wnt signaling cascades. As men- Altogether, the reviewed evidences indicate that the Wnt path- tioned, Wnt-5a and Wnt-3a have differential effects in neural way is relevant for the development of new neurons in the adult precursor cells cultured from postnatal SVZ (Pino et al., 2011). In hippocampus. The canonical Wnt/β-catenin signaling pathway this neurogenic region, the dual regulation by Wnt ligands may is important for the maintenance and self-renewal of the stem be achieved by region-specific expression of Wnt ligands during cell pool, and for progenitor cell proliferation, fate commitment the specification and maturation of olfactory bulb interneurons and differentiation. Therefore, Wnt ligands are part of the signal- in the SVZ, rostral migratory stream and olfactory bulb. Whether ing molecules in the SGZ that could regulate the progression of the same regulation occurs during neurogenesis in the adult SGZ neurogenesis. Several Wnt ligands are constantly present in the it is not known. In the hippocampus, all steps of neurogenesis adult hippocampus, but Wnt activity is also dynamically regu- occur at the dentate gyrus, where there are stem cells, progeni- lated by the expression and release of Wnt ligands and soluble tors and newborn neurons at different maturation stages in close Wnt inhibitors. This dynamic regulation of Wnt activity could proximity. Therefore, factors regulating each aspect of neurogen- be relevant for the regulation of neurogenesis under different esis should be present at the dentate gyrus. It has been proposed physiological conditions. that radial stem cells at the hippocampus have three domains that span three different anatomical layers (Fuentealba et al., 2012), ACKNOWLEDGMENTS which could allow specific microenvironments during neuroge- This work was supported by Grants from FONDECYT nesis; however, it is also plausible that signal integration of the (N◦11110012) to Lorena Varela-Nallar, FONDECYT stage-specific cues present in the niche may be given by specific (N◦1120156) and the Basal Center of Excellence in Aging and Fzreceptorsaswehavediscussed. (CONICYT-PFB12/2007) to Nibaldo C. Inestrosa.

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Birth cells into intermediate progeni- which permits use, distribution and pus. Cell. Stem Cell 1, 515–528. doi: Defects Res. C Embryo. Today 90, tors. Dev. Biol. 309, 285–297. doi: reproduction in other forums, provided 10.1016/j.stem.2007.09.002 284–296. doi: 10.1002/bdrc.20193 10.1016/j.ydbio.2007.07.013 the original authors and source are cred- Suh, H., Deng, W., and Gage, F. Varela-Nallar, L., Grabowski, C. P., Zhai,R.,Olias,G.,Chung,W.J.,Lester, ited and subject to any copyright notices H. (2009). Signaling in adult Alfaro, I. E., Alvarez, A. R., and R. A., Tom Dieck, S., Langnaese, K., concerning any third-party graphics etc.

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