REVIEW

Wnt signalling in neuronal differentiation and development

Nibaldo C. Inestrosa & Lorena Varela-Nallar

Received: 2 May 2014 /Accepted: 25 August 2014 /Published online: 19 September 2014# Springer-Verlag Berlin Heidelberg 2014

Abstract Wnts are secreted glycoproteins that play multipleroles in early development, including the differentiation ofprecursor cells. During this period, gradients of Wnts andother morphogens are formed and regulate the differentiationand migration of neural progenitor cells. Afterwards, Wntsignalling cascades participate in the formation of neuronalcircuits, playing roles in dendrite and axon development,dendritic spine formation and synaptogenesis. Finally, in theadult brain, Wnts control hippocampal plasticity, regulatingsynaptic transmission and neurogenesis. In this review, wesummarize the reported roles of Wnt signalling cascades inthese processes with a particular emphasis on the role of Wntsin neuronal differentiation and development.

Keywords Wnt signalling pathway . Neural progenitor cells .

Neuronal differentiation . Neuronal maturation . Adultneurogenesis

Introduction

Wnts are secreted signalling molecules that activate signallingcascades involved in different aspects of embryonic develop-ment including cell fate specification, polarity and migration(Clevers and Nusse 2012; Nusse and Varmus 2012). The Wntsignalling pathway is activated by Wnt ligands, which aremembers of a family of 19 secreted glycoproteins in mammalsthat bind to seven-pass transmembrane Frizzled (FZD) recep-tors to activate different signalling cascades: the canonicalWnt/β-catenin signalling pathway and the non-canonical β-catenin-independent signalling cascades (Gordon and Nusse2006) (Fig. 1). Importantly, the same ligand may activatedifferent Wnt signalling cascades depending on the receptorcontext, and activation of a specific pathway may antagonizethe activation of other pathways (Mikels and Nusse 2006).Canonical and non-canonical Wnt ligands can compete forbinding to FZD receptors, thereby causing reciprocal pathwayinhibition of both signalling pathways (Grumolato et al.2010). In addition to FZDs, other membrane proteins havebeen identified as receptors or co-receptors ofWnts, includingthe low-density lipoprotein receptor-related protein 5 (LRP5),LRP6, receptor tyrosine kinase-like orphan receptor 1(ROR1), ROR2 (Cadigan and Liu 2006; Gordon and Nusse2006; Green et al. 2008), and the receptor-like tyrosine kinaseRyk that has been implicated in axon guidance in the develop-ing nervous system (Bovolenta et al. 2006; Fradkin et al. 2009).

Soluble proteins are also important modulators of Wnt’sactions, where some of them, such as secreted FZD-relatedproteins (sFRPs), Dickkopf (DKK) proteins and Wnt inhibi-tory factor 1 (WIF1), act as inhibitors of the Wnt pathway(Cruciat and Niehrs 2013; Kawano and Kypta 2003; Niehrs2006). There are also other physiological and pharmacologi-cal mechanisms that can activate the intracellular componentof the canonical Wnt/β-catenin signalling cascade. For exam-ple, extracellular R-spondin (Rspo) proteins have been shown

N. C. Inestrosa (*)Centro de Envejecimiento y Regeneración (CARE), Departamentode Biología Celular y Molecular, Facultad de Ciencias Biológicas,Pontificia Universidad Católica de Chile, 340, P. O. Box 114-D,Santiago, Chilee-mail: ninestrosa@bio.puc.cl

N. C. InestrosaCenter for Healthy Brain Ageing, School of Psychiatry, Faculty ofMedicine, University of New South Wales, Sydney, Australia

N. C. InestrosaCentro de Excelencia en Biomedicina de Magallanes (CEBIMA),Universidad de Magallanes, Punta Arenas, Chile

L. Varela-Nallar (*)Center for Biomedical Research, Faculty of Biological Sciences andFaculty of Medicine, Universidad Andres Bello, Republica 239,8370146 Santiago, Chilee-mail: lorena.varela@unab.cl

Cell Tissue Res (2015) 359:215–223DOI 10.1007/s00441-014-1996-4

to bind LGR4, LGR5 and LGR6 G-protein coupled receptorsto physiologically activate this pathway (Carmon et al. 2011;Glinka et al. 2011). In addition, the long-standing pharmaco-logical agent lithium inhibits glycogen synthase kinase-3β(GSK-3β) intracellularly, thereby stabilizing β-catenin to ac-tivate the pathway independently of ligand–receptor interac-tions (Toledo and Inestrosa 2010; Valvezan and Klein 2012).

The activation of the canonical Wnt/β-catenin signallingcascade involves the formation of a Wnt–LRP–FZD complexthat activates the scaffold protein Dishevelled (Dvl) andcauses the dissociation of a multiprotein destruction complex,consisting of enzymes that phosphorylate and target β-catenin

for proteasomal degradation when the pathway has not beenactivated (Hart et al. 1999; Liu et al. 2002). Consequently, β-catenin accumulates in the cytoplasm and translocates to thenucleus where it interacts with members of the TCF/LEF1family of transcription factors to regulate the expression ofWnt target genes (Arrazola et al. 2009; Clevers and Nusse2012; Nusse and Varmus 2012). In the multiprotein destruc-tion complex, β-catenin is phosphorylated by casein kinase1α (CK1α) and GSK-3β which are associated with the scaf-fold protein Axin and adenomatous polyposis coli (APC)(Hart et al. 1998; Ikeda et al. 1998; Kishida et al. 1998;Sakanaka et al. 1998).

Fig. 1 The Wnt signalling pathway. Canonical and non-canonical sig-nalling cascades. Binding of a Wnt ligand to a Frizzled (FZD) receptoractivates different signalling cascades. In the canonical Wnt/β-cateninsignalling pathway (left) theWnt ligand also interacts with the co-receptorlow density lipoprotein-related protein 5 or 6 (LRP5/6) to activate theprotein Dishevelled (Dvl) and induce the stabilization of β-catenin bypreventing its phosphorylation by glycogen synthase kinase-3β (GSK-3β) in a multiprotein complex composed also of the scaffold protein Axinand adenomatous polyposis coli (APC). Consequently, β-catenin accu-mulates in the cytoplasm and enters the nucleus where it interacts with thetranscription factors TCF/LEF to induce the transcription of Wnt target

genes. In the non-canonical Wnt/Ca2+ signalling cascade (middle), acti-vation of the pathway triggers the activation of trimeric G proteins andsubsequently phospholipase C (PLC), increasing inositol triphosphate(IP3). IP3 induces the release of Ca2+ from the endoplasmic reticulum(ER), which then induces the activation of calcium/calmodulin-dependentprotein kinase II (CamKII) and protein kinase C (PKC). In the non-canonical Wnt/PCP signalling cascade (right), activation of the pathwayleads to the activation of the small GTPases Rho and Rac leading to theactivation of Rho-associated protein kinase (ROCK) and Jun N-terminalkinase (JNK) to regulate cytoskeleton dynamics

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The Wnt/FZD interaction can also activate the non-canonical Wnt/PCP or Wnt/Ca2+ pathways (Fig. 1). In theWnt/PCP pathway, the phosphorylation of Dvl causes theactivation of the small GTPases Rho and Rac and, conse-quently, the downstream Jun N-terminal kinase (JNK), whichregulates cytoskeleton dynamics (Gordon and Nusse 2006;Rosso and Inestrosa 2013; Rosso et al. 2005). In contrast, theWnt/Ca2+ pathway is almost exclusively a G-protein-dependent signalling pathway (Kohn and Moon 2005). Theactivation of the Wnt/Ca2+ pathway requires binding of Wntto FZD on the cell surface membrane to trigger stimulation ofheterotrimeric G-proteins (Slusarski et al. 1997a; Slusarskiet al. 1997b), which activate phospholipase-C (PLC). PLCcauses an increment in intracellular Ca2+ release that decreasescyclic guanosine monophosphate (cGMP) and activates theprotein kinases Ca2+/Calmodulin-dependent protein kinase II(CaMKII) and protein kinase-C (PKC) (Kohn and Moon2005; Montcouquiol et al. 2006; Veeman et al. 2003). Inaddition, it activates the transcription factor NFAT to inducethe transcription of target genes.

In the nervous system, Wnt signalling cascades are impor-tant for the formation of neuronal circuits. During develop-ment, Wnt signalling regulates self-renewal, maintenance anddifferentiation of neural progenitor cells (Hirabayashi et al.2004; Machon et al. 2007; Munji et al. 2011) and regulates thedevelopment of the cortex and hippocampus (Li and Pleasure2005; Machon et al. 2007). Wnts not only regulate earlyembryonic development but are also key regulators of lateembryonic and postnatal development of the central nervoussystem (CNS) (Inestrosa and Arenas 2010; Oliva et al. 2013).Various Wnt ligands regulate synaptic development and func-tion, including the formation and maturation of pre- andpostsynaptic sites and neurotransmission. Members of theWnt family of secreted signalling proteins are implicated inevery step of neural development. During vertebrate develop-ment, a Wnt signalling gradient that is high in the posteriorand low in the anterior is critical for the proper specification ofthe anterior–posterior axis of the neural plate (Kiecker andNiehrs 2001). In fact, several studies have demonstrated thatinhibition of Wnt signalling in the anterior, as well as theactivation of Wnt signalling in the posterior, is required forproper anterior-posterior patterning of the early CNS (Esteveet al. 2000; Glinka et al. 1998; Houart et al. 2002; Kazanskayaet al. 2000). During early development, after the neural plate isspecified, it invaginates to form the neural tube, a process thatis complete once the paired neural folds adhere at the dorsalmidline, and which is required for the development of thespinal cord and brain. Neural tube defects cause conditionslike spina bifida and anencephaly. It has been determined thatthe Wnt/PCP signalling pathway is relevant for neural tubeclosure and is involved in neural tube defects (Curtin et al.2003; Wen et al. 2010). Also, a role for the Wnt/β-cateninpathway in neural tube closure is indicated by the presence of

neural tube defects in mice with mutations in LRP6 (Carteret al. 2005) and Axin 1 (Perry et al. 1995), and in micecarrying ablated TCF–β-catenin interactions (Wu et al. 2012).

Neural progenitor cells that make up the neural tube pro-liferate, differentiate and migrate to form the many neuronalganglia, nuclei, and layers of the CNS. The Wnt/β-cateninsignalling pathway has been associated with both proliferationand specification of neural progenitor cells. It has been deter-mined that Wnt-1 and Wnt-3a ligands are expressed at thedorsal midline of the developing neural tube and are requiredfor the formation of brain structures; mutant analyses in miceshow that the midbrain is absent whenWnt-1 is not expressed(McMahon and Bradley 1990; Thomas and Capecchi 1990),and the hippocampus is absent when Wnt-3a is not expressed(Lee et al. 2000). The Wnt-3a mutant shows decreased celldivision within the hippocampal neuroepithelium; however,there remain small hippocampal subfields. This implies thatthe Wnt-3a ligand primarily regulates proliferation of hippo-campal neural precursor cells (Lee et al. 2000). Duringcorticogenesis, the levels of Wnt activity have been shownto be important in controlling the switch between proliferationand differentiation of progenitor cells (Bielen and Houart2014), which depends on β-catenin. Increased stabilizationof β-catenin decreases cell cycle exit in neural precursors,while decreased Wnt/β-catenin signalling is associated withdifferentiation (Chenn and Walsh 2002; Mutch et al. 2010).Later in development, Wnt/β-catenin signalling induces neu-ral differentiation. In cortical neural precursor cells, Wnt/β-catenin signalling inhibits the self-renewal capacity of progen-itors and promotes neuronal differentiation (Hirabayashi et al.2004). This effect on differentiation is stage-specific, since itis not observed in neural precursor cells at earlier develop-mental stages (Hirabayashi et al. 2004; Munji et al. 2011).Thus, Wnt signalling regulates both self-renewal and subse-quent cell fate specification of neuronal progeny, and theseeffects depend on transcriptional regulation mediated by theWnt/β-catenin signalling pathway. The effect on proliferationinvolves the transcriptional control of genes that regulate thecell cycle (reviewed in Niehrs and Acebron 2012) and neuro-nal differentiation involves the regulation of the expression ofproneural genes such as the neurogenin 1 gene (Hirabayashiet al. 2004).

The relevance of the Wnt signalling pathway in normalbrain function is supported by the fact that its deregulation hasbeen linked to different pathologies that affect the CNS,including mental disorders, mood disorders and neurodegen-erative diseases (De Ferrari and Moon 2006; Inestrosa et al.2012; Inestrosa and Varela-Nallar 2014; Lovestone et al.2007; Oliva et al. 2013). Interestingly, the Wnt signallingpathway shows neuroprotective properties in Alzheimer’sdisease (AD), a neurodegenerative illness characterized by aprogressive loss of cognitive abilities including learning andmemory (Ballard et al. 2011) that has been associated with an

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impairment in Wnt signalling (De Ferrari and Inestrosa 2000;Inestrosa and Arenas 2010). In cultured hippocampal neuronsand in hippocampal slices, Wnts show neuroprotective prop-erties against the toxicity of the amyloid-β (Aβ) peptide(Alvarez et al. 2004; Cerpa et al. 2010; Chacon et al. 2008;De Ferrari et al. 2003), which is associated with AD patho-genesis. This was supported by in vivo experiments showingthat the activation of the Wnt signalling pathway in a doubletransgenic mouse model of AD reduces spatial memory im-pairment and the histopathological hallmarks of the disease(Toledo and Inestrosa 2010), indicating that in vivo modula-tion of the Wnt signalling pathway may have therapeuticvalue in some pathological conditions.

Wnt signalling in neuronal maturation

Compelling evidence indicates that Wnt signalling cascadesare important for the regulation of several aspects of neuronaldevelopment. Neuronal polarization, axonal and dendriticdevelopment and synaptogenesis are crucial for the formationof neuronal circuits. Studies have shown that the Wnt signal-ling pathway is involved in all these steps of neuronal devel-opment. In cerebellar neurons, it has been shown that Wnt-7ainduced axon and growth cone remodelling (Hall et al. 2000;Lucas and Salinas 1997). Wnt-mediated changes in growthcone remodelling involve changes in microtubule organiza-tion through the regulation of APC (Purro et al. 2008).Wnt-5aalso regulates axonal behavior in sympathetic and corticalneurons (Bodmer et al. 2009; Li et al. 2009). Interestingly, incortical neurons, Wnt-5a stimulates axonal outgrowth andrepulsive axon guidance through different receptors. Axonaloutgrowth is mediated by the Ryk receptor, whereas axonalrepulsion requires both Ryk and FZD receptors (Li et al.2009). Recently, we determined that FZD5 regulates axondevelopment (Slater et al. 2013). Moreover, by gain- andloss-of-function experiments, we determined that FZD5 reg-ulates a very early event in neuronal development: the estab-lishment of neuronal polarity (Fig. 2). In cultured neurons,FZD5 shows a very polarized distribution being mainly pres-ent in the peripheral zone of growth cones. Overexpression ofFZD5 induces a loss of polarized distribution of the receptorand induces a mislocalization of axonal proteins, while FZD5knockdown induces a loss of axonal proteins (Slater et al.2013). These data suggest that FZD5 is important for neuronalpolarity. In addition, when the receptor is overexpressed afterthe acquisition of neuronal polarity, it does not revert polari-zation but alters neuronal morphogenesis by decreasing axo-nal length and increasing dendritic length and arborisation viaa JNK-dependent mechanism (Slater et al. 2013). Severalstudies have shown the involvement of Wnt signalling com-ponents in dendrite morphogenesis. In hippocampal neurons,β-catenin is a critical mediator of dendritic morphogenesis.

This effect of β-catenin is independent of gene transcriptionand is required for dendritic growth induced by depolarization(Yu and Malenka 2003). Another study demonstrated that, inhippocampal neurons, activation of NMDA receptors in-creases the expression of Wnt-2, which then stimulates den-dritic arborization (Wayman et al. 2006), indicating the in-volvement of Wnt in activity-dependent dendritic develop-ment. Wnt-7b also regulates dendritic arborization, and thiseffect is mediated by a non-canonical Wnt signalling cascadethat involves JNK activation (Rosso et al. 2005).

In addition to the participation in neuronal polarization andmorphogenesis, it is known that Wnt signalling regulates syn-apse formation and neurotransmission. Electrophysiologicalrecordings in rat hippocampal slices showed that a blockadeof Wnt signalling impairs long-term potentiation (LTP) (Chenet al. 2006), indicating the importance of this signalling path-way in synaptic plasticity (Vargas et al. 2014). Importantly, theexpression and release of Wnts are regulated by neuronalactivity (Chen et al. 2006; Wayman et al. 2006), supportingthe notion that these ligands may play a role during neuronaltransmission. Regarding the synaptic effects of Wnts, severalyears ago it was shown in cerebellar neurons that Wnt-7aregulates the clustering of the synaptic vesicle protein synapsinI (Hall et al. 2000; Lucas and Salinas 1997). The effect of Wntsignalling on presynaptic assembly has also been observed inhippocampal neurons, in which Wnt-7a, Wnt-3a and Wnt-7bincrease the presynaptic puncta and the synaptic vesicle cycle(Ahmad-Annuar et al. 2006; Cerpa et al. 2008; Davis et al.2008). Moreover, electrophysiological recordings on adult rathippocampal slices demonstrated that Wnt-7a increases neuro-transmitter release in CA3-CA1 synapses (Cerpa et al. 2008).The presynaptic effects of Wnts may be mediated by Wntreceptors located at the synaptic region. In hippocampal neu-rons, we determined that the Wnt receptor FZD1 is present atthe presynaptic site where it regulates the presynaptic assembly(Varela-Nallar et al. 2009). Also, FZD5 was shown to mediatesynaptogenesis induced by Wnt-7a (Sahores et al. 2010).These findings have demonstrated a relevant role for the Wntsignalling pathway in presynaptic differentiation and function.

In addition, non-canonical Wnt signalling cascades havebeen associated with the postsynaptic apparatus.Electrophysiological recordings showed that Wnt-5a in-creases the amplitude of field excitatory postsynaptic poten-tials (fEPSP) and upregulates synaptic NMDAR currents,facilitating the induction of LTP (Cerpa et al. 2010, 2011), atwo-step effect that is independently mediated by proteinkinase C (PKC) and JNK (Cerpa et al. 2011). At the structurallevel, Wnt-5a modulates postsynaptic assembly, increasingclustering of the postsynaptic density protein-95 (PSD-95)(Farias et al. 2009), which is a key scaffold protein of thepostsynaptic density.

TheWnt signalling pathway also modulates dendritic spinemorphogenesis in cultured hippocampal neurons, an early

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event in synapse formation that is crucial for synaptic plastic-ity. We observed that Wnt-5a treatment induces an increase indendritic protrusions that mature into dendritic spines (Varela-Nallar et al. 2010a). Interestingly, the effect on dendriticprotrusions was not observed by treatment with Wnt-3a, indi-cating that there is some level of specificity for this effect(Varela-Nallar et al. 2010a). Time-lapse imaging revealed thatWnt-5a induces the formation of new dendritic spines andincreases the size of preexisting ones (Varela-Nallar et al.2010a). Another ligand that regulates dendritic spines isWnt-7a, which was shown to increase the density andmaturityof dendritic spines through a mechanism involving CamKII(Ciani et al. 2011), suggesting that the non-canonical Wnt/Ca2+

signalling cascade is involved in this effect. Both Wnt-5a andWnt-7a increase intracellular Ca2+ concentration in neurons(Ciani et al. 2011; Varela-Nallar et al. 2010a), suggesting thata common Ca2+-dependent mechanism may be involved inthe Wnt-mediated regulation of dendritic spines. A potentialreceptor for the effect of Wnts on dendritic spines is ROR2,which is located in dendritic spines (Alfaro et al., unpublishedresults). We have determined that ROR2 is important for thematuration and maintenance of dendritic spines in hippocam-pal neurons (Fig. 3), and, interestingly, this receptor mediatedan inhibitory effect of Wnt-5a in a voltage-gated K+ current

(Parodi et al., unpublished results), indicating that this may bethe receptor or co-receptor mediating the described postsyn-aptic effects of Wnt-5a.

Wnt signalling in adult neurogenesis

In the adult brain, the generation of new neurons continuesmainly in two regions, the SVZ in the wall of the lateralventricles and the SGZ in the dentate gyrus of the hippocam-pus (Alvarez-Buylla and Garcia-Verdugo 2002; Zhao et al.2008). In these two neurogenic regions, neural stem cells(NSC) proliferate and differentiate into neuroblasts that inthe SVZ migrate through the rostral migratory stream to theolfactory bulb where they became interneurons, and in theSGZ mature into granule neurons that become integrated intothe granule cell layer (Ming and Song 2011; Zhao et al. 2008).

Many signalling cascades are involved in the regulation ofthe different steps of neurogenesis being important for theproper balance between the maintenance of the NSC pooland for the differentiation and maturation of newborn neurons(Faigle and Song 2013; Schwarz et al. 2012; Suh et al. 2009).During recent years, increasing evidence has supported a rolefor the Wnt/β-catenin pathways in the regulation of adult

Fig. 2 FZD5 in neuronal polarityand morphogenesis. FZD5 islocated in the peripheral zone ofaxonal growth cones. Gain- andloss-of-function experimentsdemonstrate that FZD5 isimportant for neuronal polarity.Overexpression of FZD5 inneurons that are already polarizeddecrease the total length of axons,a process partially prevented byinhibition of JNK, suggesting theWnt/PCP pathway modulatesaxon behavior

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neurogenesis (Varela-Nallar and Inestrosa 2013). In 2005, thegroup of Fred Gage determined in in vivo experiments thatoverexpression of Wnt-3 in the dentate gyrus increases cellproliferation and the generation of new neurons, while inhibi-tion of the Wnt signalling pathway reduces proliferation andneurogenesis (Lie et al. 2005). In that study, it was shown thatWnts derived from hippocampal astrocytes induce the differ-entiation of rat adult hippocampal progenitors (AHPs) and thatAHPs express Wnt signalling components. Later on, anotherstudy demonstrated in vitro that rat AHPs express several Wntligands and receptors, and also that there is an autocrine Wntstimulation that supports the proliferation and multipotency ofAHPs, and therefore it may be relevant for NSC maintenance(Wexler et al. 2009). More recently, it was shown that Wnt-7ais important for multiple steps of adult neurogenesis includingNSC self-renewal, neural progenitor cell proliferation, neuro-nal differentiation and maturation (Qu et al. 2013). Theseeffects of Wnt-7a involve the regulation of cyclin D1 andneurogenin 2 genes, involved in cell cycle control and neuro-nal differentiation, respectively (Qu et al. 2013).

In addition to Wnts, multiple components and regulators ofthe Wnt signalling pathway have been associated with adultneurogenesis. GSK-3β is involved in the regulation ofneurogenesis mediated by disrupted in schizophrenia 1(DISC1) (Inestrosa et al. 2012). This protein inhibits GSK-3β,and the impairment in progenitor cell proliferation caused byDISC1 knock-down can be rescued by overexpression of stabi-lizedβ-catenin (Mao et al. 2009) In vivo, the impairments in cellproliferation observed in the adult dentate gyrus by DISC1 lossof function can be rescued by administration of a GSK-3βinhibitor (Mao et al. 2009). In the SVZ, retrovirus-mediatedexpression of a stabilized β-catenin induces the proliferation oftype C cells (Adachi et al. 2007), and expression of Axin, a partof the protein complex that mediates the phosphorylation anddegradation of β-catenin, decreases cell proliferation (Qu et al.2010). Taken together, this evidence supports a role for thecanonical Wnt signalling pathway in NSC proliferation.

Soluble Wnt inhibitors have also been associated with adultneurogenesis. Dkk1 and sFRP3 are negative regulators of adultneurogenesis. Dkk1 prevents the activation of the canonicalWnt/β-catenin signalling cascade by preventing the formationof the FZD/LRP complex, while sFRP3 binds to Wntspreventing their interaction with their receptors (Cruciat andNiehrs 2013). Deletion of Dkk1 and sFRP3 increaseneurogenesis and dendrite complexity of newborn neurons(Jang et al. 2013; Seib et al. 2013). Interestingly, both Wntinhibitors are regulated by physiological stimuli that regulateneurogenesis, suggesting a physiological role for both proteinsand for the Wnt signalling pathway in the regulation ofneurogenesis in the adult brain. A reduction in sFRP3 is ob-served during exercise and electroconvulsive stimulation, sug-gesting that this reduction may be important for the increase inneurogenesis observed in both conditions (Jang et al. 2013). Onthe other hand, the expression of Dkk1 is increased duringaging (Seib et al. 2013), suggesting that it may be involved inthe decline of neurogenesis observed in different species duringlifespan (Knoth et al. 2010; Kuhn et al. 1996; Leuner et al.2007; Varela-Nallar et al. 2010b). During aging, a decline in thelevels of Wnt-3 and Wnt-3a in the dentate gyrus was alsoreported (Okamoto et al. 2011), which may also underlie thedecline in neurogenesis. In addition, canonicalWnt signalling isincreased in vivo by exposure to chronic hypoxia, concomi-tantly with an increase in cell proliferation and neurogenesis inthe SGZ of adult mice (Varela-Nallar et al. 2014). This suggeststhat the Wnt signalling pathway may also be involved in theeffect of mild hypoxia on neurogenesis.

The mechanisms involved in the regulation of adultneurogenesis by the Wnt signalling pathway may involvethe transcription of proneural Wnt target genes. It has beendetermined that the expression of the transcription factorsNeuroD1 and Prox1 is regulated by the canonical Wnt signal-ling pathway (Karalay et al. 2011; Kuwabara et al. 2009).NeuroD1 is important for neurogenesis in the SGZ and SVZ

Figure 3 ROR2 is involved in dendritic spine development. Wnt ligandsregulate spinogenesis in hippocampal neurons through activation of non-canonical Wnt pathways. Recently the tyrosine kinase receptor ROR2,which is located in dendritic spines, has been implicated in this process(unpublished results). In dendritic spines, ROR2 may act either as areceptor or co-receptor of FZD to activate non-canonical signallingpathways

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in the adult brain (Gao et al. 2009), and Prox1 is important forthe differentiation and survival of newborn granule cells(Karalay et al. 2011). Both transcription factors identified asWnt target genes might be important for the positive effect ofthe Wnt signalling pathway in adult neurogenesis.

Concluding remarks

The Wnt signalling pathway plays pivotal roles during theformation, maintenance and function of the CNS, having awide range of functions that include neuronal differentiation,development and maturation. There are many Wnt proteinsand severalWnt receptors and co-receptors that in conjunctionpaint a complex picture that might be relevant for the fineregulation of neuronal circuit formation and functioning.More recent evidence has shown that the Wnt signallingpathway also regulates the formation of new neurons in theadult brain, where it regulates the proliferation and differenti-ation of neural progenitor cells. Considering all the neuronalprocesses that are regulated by the Wnt signalling pathway inbrain neurons, it can be expected that additional roles for thispathway in the development, maturation and integration ofadult-born neurons might be unveiled in the near future.

We thank Felipe G. Serrano (CARE, Department of Cell and MolecularBiology, P. Catholic University of Chile) for artwork. This work wassupported by Grants from FONDECYT (No. 1120156) and the BasalCenter of Excellence in Science and Technology (CONICYT-PFB12/2007) to N.C.I. and by a Grant from FONDECYT (No. 11110012) toL.V.-N.

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