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European Journal of Neuroscience

European Journal of Neuroscience, Vol. 33, pp. 1–8, 2011 doi:10.1111/j.1460-9568.2010.7483.x

REVIEW The Wnt ⁄b- signaling pathway in the adult

Lin Zhang, Xinyu Yang, Shuyuan Yang and Jianning Zhang Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurology Institute, Tianjin Key Laboratory of Injuries,Variations and of , Tianjin 300052, China

Keywords: differentiation, migration, proliferation, synaptogenesis

Abstract The Wnt ⁄ b-catenin signaling pathway plays an important role in neural development, b-catenin is a central component of the Wnt ⁄ b- catenin signaling pathway, which not only performs the function of transmitting information in the , but also translocates to the nucleus-activating target . The target in neural tissues have not been fully revealed, but the effects of the Wnt ⁄ b-catenin signaling pathway in adult neurogenesis have been demonstrated by ongoing research, which are significative to the basic research and treatment of neuronal degeneration diseases. Here, we review key findings to show the characteristics of b-catenin and its pivotal nature in the Wnt ⁄ b-catenin signaling pathway in a number of molecular studies. We also review current literature on the role of b-catenin in adult neurogenesis, which consists of an active process encompassing the proliferation, migration, differentiation and final synaptogenesis.

Introduction The is a highly conserved signaling pathway. enhancer factor (TCF ⁄ LEF) family of transcription factors, leading to The components of this pathway reveal highly homologous from activation of target genes (Stadeli et al., 2006; Willert & Jones, 2006). Drosophila to mammal. The initial finding of the Wnt gene was The Wnt ⁄ b-catenin signaling pathway plays a vital role in unexpected and provided a significant revelation for further research. neural development. Its signaling has been demonstrated to participate In 1982, Nusse and Varmus found that the mouse int1 gene is a in axis formation, midbrain development and oncogenesis to name preferential integration site for the mouse mammary tumor virus in some of the most recognized functions (McMahon & Bradley, 1990; virally induced breast tumors. Subsequently, Drosophila Wingless McMahon, 1993; Nusse, 2001; Miller, 2002; Logan & Nusse, 2004; (Wg), which controls segment polarity during larval development Polakis, 2007). The inactivation of b-catenin results in specific (Nusslein-Volhard & Wieschaus, 1980), was shown to be a fly developmental brain defects (Brault et al., 2001). In contrast, the homolog of Int1 (Rijsewijk et al., 1987). Uniting the names of these activation of b-catenin leads to amplification of the neural two genes, this gene was renewed to Wnt, which encodes some kinds progenitor pool (Chenn & Walsh, 2002; Megason & McMahon, of secretary glycoprotein to activate the Wnt signaling pathway. Three 2002). In several pathologies an association with the Wnt signaling different pathways are demonstrated to be activated upon Wnt receptor pathway has been found (Moon et al., 2004). The disorder of activation: the canonical Wnt ⁄ b-catenin cascade, the non-canonical signaling is associated with several pathologies, such as Alzheimer’s planar polarity pathway and the Wnt ⁄ Ca2+ pathway. The disease (AD; De Ferrari & Inestrosa, 2000; Inestrosa et al., 2000; De canonical Wnt ⁄ b-catenin pathway is the best understood and is the Ferrari et al., 2007), (Lovestone et al., 2007), autism primary subject of this review. (De Ferrari & Moon, 2006) and cancer (Rubinfeld et al., 1993; A crucial component of the canonical Wnt ⁄ b-catenin pathway is Polakis, 2007).These diseases all have a link with adult neurogenesis, b-catenin, a multifunctional that can function in gene transcrip- thus it is obvious that the Wnt ⁄ b-catenin signaling pathway plays a tion and cell adhesion (Nelson & Nusse, 2004). b-Catenin was first role in adult neurogenesis. Subsequently we will review the literature isolated as a protein associated with the intracellular domain of of Wnt ⁄ b-catenin signaling, and the diverse points of connection E-, a component of the (Aberle et al., 1996). between canonical Wnt ⁄ b-catenin signaling and adult neurogenesis. In the canonical Wnt ⁄ b-catenin pathway, the interaction between Wnt protein and receptors triggers recruitment of Axin to the plasma membrane, resulting in the inhibition of b-catenin and The b-catenin and Wnt ⁄ b-catenin signaling pathway degradation (Cadigan & Liu, 2006; Huang & He, 2008). Consequently, b-Catenin, as a homologous molecule with Drosophila segment b-catenin accumulates in the cytoplasm and then translocates into the polarity gene armadillo (Arm), is the central protein in the Wnt nucleus where it forms a complex with the T-cell factor ⁄ lymphoid signaling pathway. It was initially discovered as a component of the adherens junction, which links E-cadherin to a-catenin and then Correspondence: Dr X. Yang, as above. associates with . Aside from this function, b-catenin is a E-mail: [email protected] key effector in the Wnt signaling pathway, serving as a downstream Received 26 June 2010, revised 21 September 2010, accepted 24 September 2010 .

ª 2010 The Authors. European Journal of Neuroscience ª 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd 2 L. Zhang et al.

The structure and characteristics of b-catenin Frizzled (Fzd) and the co-receptor low-density lipoprotein receptor- The primary structure of the b-catenin protein comprises a 42-amino related protein 5 ⁄ 6 (LRP5 ⁄ 6). The classical view of the canonical acid central domain (Arm repeats), a 130-amino acid amino-terminal Wnt ⁄ b-catenin signaling transduction pathway (Fig. 1) implies the domain and a 100-amino acid carboxy-terminal domain (Willert & presence of an extracellular secreted Wnt ligand that interacts with the Nusse, 1998). The central domain of b-catenin consists of 12 receptor protein Fzd, which is a member of a family of seven-pass imperfect repeats, which form three a-helices that are connected by transmembrane . The Wnt-Fzd receptor complex forms a short loops, reorienting the polypeptide by 90. The final structure of ternary cell surface complex with the co-receptor LRP5 ⁄ 6 (Tamai the central domain is a tightly packed series of interacting a-helices et al., 2000). Thus, the Wnt signaling is transduced into cytoplasm. that form a rigid right-handed super helix. This generates a shallow This then activates Dishevelled (Dvl) usually by phosphorylation, groove lined with basic amino acids that confer on the groove an which, in turn, inactivates GSK-3b – a key modulator of this pathway. overall positive charge (Huber et al., 1997). This positively charged Wnt signaling regulates GSK-3b activity by physically displacing groove may serve as a binding surface for several proteins, including complex GSK-3b from a member of regulatory binding partners, TCF (Behrens et al., 1996; Huber et al., 1996; Molenaar et al., 1996; consequently preventing the phosphorylation and degradation of Brunner et al., 1997; van de Wetering et al., 1997), adenomatous b-catenin (Toledo et al., 2008). polyposis coli (APC; Rubinfeld et al., 1993) and adherens junction In the absence of Wnt, the signaling poll of b-catenin is maintained protein E-cadherin (Hulsken et al., 1994; Orsulic & Peifer, 1996). at a low level, through degradation (Dale, 1998; Logan & Nusse, The function of each structure of b-catenin in neuronal development 2004). b-Catenin is targeted for ubiquitination by the b-transducing of adult mammal is still unclear, and the related researches mainly repeat-containing protein and is then degraded by the proteosome. concentrate on Drosophila and Xenopus. It has demonstrated that each b-Catenin is phosphorylated by the ⁄ threonine kinases casein domain of b-catenin plays an independent role in the Wnt signaling kinase 1 and GSK-3b. Phosphorylation of b-catenin occurs in a pathway. Previously, Funayama et al. reported that overexpression of multiprotein complex (the destruction complex; Chen et al., 2000), b-catenin in the ventral side of the early Xenopus embryo, by injection comprising Axin, APC and diversin. Upon receipt of a Wnt signal, of synthetic b-catenin mRNA, induces the formation of a complete Dvl prevents degradation of b-catenin through recruitment of secondary body axis. Furthermore, an analysis of b-catenin deletion GSK-3b-binding proteins ⁄ Frat-1, which displace GSK-3b from the constructs demonstrates that the internal Arm repeat region is both destruction complex (Toledo et al., 2008). As a consequence, stable, necessary and sufficient to induce axis duplication (Funayama et al., non-phosphorylated b-catenin accumulates and translocates into the 1995). It is noteworthy that nuclear accumulation of the Arm repeat nucleus. domain of b-catenin retains potent signaling activity, which interacts Stabilized b-catenin enters the nucleus and associates with with some downstream protein targets that leads ultimately to a change TCF ⁄ LEF transcription factors via physically displaced Groucho in neuronal development. from TCF ⁄ LEF (Daniels & Weis, 2005), leading to the transcription of In the amino terminus of b-catenin, there are four potential Wnt target genes, such as cyclin D1, PPARd and engrailed (Logan & glycogen-synthasekinase-3b (GSK-3b) phosphorylation sites (Cadi- Nusse, 2004), and many others (http://www.stanford.edu/~rnusse/ gan & Nusse, 1997). Mutation of these sites led to a b-catenin that is pathways/targets.html). In the CNS, these targets include proteins more stable than wild-type b-catenin and considerably more potent in involved in neural patterning, such as the caudal-type homeodomain secondary axis formation in Xenopus (Yost et al., 1996). Deletions at transcription factors 1 (CDX1; Ikeya & Takada, 2001) and engrailed-1 the amino terminus of Arm (removing the four serine ⁄ threonine (Danielian & McMahon, 1996) during mid-brain development and residues) result in a constitutively active Arm protein (Zecca et al., EMX2 dorsal telencephalic development (Theil et al., 1999), and may 1996; Pai et al., 1997). Besides, the interaction of b-catenin with also include proliferation-promoting genes such as c-myc and cyclin a-catenin occurs via the amino terminus region of b-catenin (Aberle D1 (He et al., 1998; Shtutman et al., 1999; Tetsu & McCormick, et al., 1994; Oyama et al., 1994; Rubinfeld et al., 1995; Orsulic & 1999; Coyle-Rink et al., 2002). Peifer, 1996), and the amino terminal deletion, that fails to bind Furthermore, b-catenin may also be actively transported back to the a-catenin, still has the potential capacity to induce axis duplication cytoplasm by either an intrinsic export signal or as cargo of Axin (Funayama et al., 1995). (Cong & Varmus, 2004) or APC (Rosin-Arbesfeld et al., 2000) that So far, the function of the carboxyl terminus has not been studied in shuttle between cytoplasm and nucleus (Clevers, 2006). Although the detail, it is possible that the carboxyl terminus is required for this early mechanism of the Wnt ⁄ b-catenin signaling pathway is detailed and upstream step in the pathway, whereas the repeat domain of b-catenin complete, the subsequent expression of the target genes which impact might bypass the early steps in a signaling pathway and act directly on human biology is unclear, and the molecule involved in this (Funayama et al., 1995). Moreover, there seems to be an opinion that pathway also requires further investigation. the carboxyl terminus contains a transcriptional activation domain (Willert & Nusse, 1998) that plays a role in activating the downstream target gene. Wnt ⁄ b-catenin signaling in adult neurogenesis Although those theories have not been demonstrated in mammals, those studies form the stepping stones for further research to Adult neurogenesis is generally considered an active process encom- better understand the function of each structure of b-catenin in passing the proliferation and cell fate specification of adult neural neuronal development and enlighten us to do further work in adult progenitors, and their subsequent differentiation, maturation, naviga- neurogenesis. tion and functional integration into the existing neuronal circuitry (Duan et al., 2008). In the adult CNS, active neurogenesis occurs in two discrete ‘neurogenic’ regions: the (SGZ) of the (DG) in the and the The Wnt ⁄ b-catenin signaling pathway (SVZ) of the in the forebrain (Alvarez-Buylla & Lim, The first step of the activation of the Wnt ⁄ b-catenin signaling pathway 2004; Lie et al., 2004). In this section we will review evidence for the is the interaction between Wnt proteins and the receptor protein role of the Wnt ⁄ b-catenin signaling in adult neurogenesis, including

ª 2010 The Authors. European Journal of Neuroscience ª 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1–8 The Wnt ⁄ b-catenin signaling pathway 3 studies concerning neural stem cells proliferation, migration of (Scholzke & Schwaninger, 2007). It is well known that b-catenin is precursor cells, differentiation and synaptic development (Fig. 2). both a component of the transmission and a transcription factor in this pathway. Its nuclear (transcription) actions induce proliferation of undifferentiated precursor cells by making them re-enter the cell cycle Wnt ⁄ b-catenin signaling in the proliferation of neural stem cells rather than differentiate (Brembeck et al., 2006). If stabilized b-catenin The effects of Wnt ⁄ b-catenin signaling depend on which Wnt family is overexpressed in transgenic mice, the brain is enlarged, and the members are involved, as well as on the specific time point and cellular neural precursor population is expanded (Chenn & Walsh, 2002). localization of activation. In the early stages of embryonal develop- Strong evidence is accumulating for a role of Wnt ⁄ b-catenin ment, activation of the Wnt ⁄ b-catenin signaling pathway supports signaling in adult neurogenesis, in particular the proliferation of neural precursor cells in a pluripotent state and maintains their self-renewal stem cells. Lie et al. tested whether Wnt ⁄ b-catenin signaling regulates

ABWnt Wnt LRP5/6 Frizzled LRP5/6 Frizzled

Dvl Axin

GSK-3β Axin A A GSK-3β P CK1 P P β-Catenin C C Ub β P β -TrCP P P -Catenin β-Catenin β-Catenin Ub β Ub -Catenin Ub β-Catenin β-Catenin Proteasomal Degradation

Nucleus Nucleus Wnt target Wnt target β Gr TCF/LEF genes -Cate TCF/LEF genes

Fig. 1. The canonical Wnt signaling pathway. (A) In the absence of Wnt protein, the degradation complex, comprising Axin, adenomatous polyposis coli (APC), glycogen-synthasekinase-3b (GSK-3b) and casein kinase 1 (CK1) maintains b-catenin in a low level. GSK-3b phosphorylates b-catenin molecules. b-Transducing repeat-containing protein (b-TrCP) degrades b-catenin, and it is eventually degraded by the proteosome. Wnt target genes are inhibited through the action of the T-cell factor ⁄ lymphoid enhancer factor (TCF ⁄ LEF)–Groucho (Gr) complex by the lack of b-catenin in the nucleus. (B) In the presence of Wnt protein, Wnt binds to the seven-transmembrane-domain protein Frizzled (Fzd) and to its co-receptors, low-density lipoprotein receptor-related protein (LRP)5 ⁄ 6 triggers activation of the cytoplasmic scaffold protein Dishevelled (Dvl); then the activated Dvl interacts with Axin ⁄ APC ⁄ GSK-3b and leads to the inhibition of GSK-3b. Inhibition of GSK-3b results in the accumulation of stabilized b-catenin in the cytoplasm and translocation to the nucleus. In the nucleus, b-catenin interacts with the TCF ⁄ LEF and forms the transcriptional complex leading to the transcriptional activation of Wnt target genes which are involved in cell fate and ⁄ or proliferation.

β-Catenin low expression Newly generated mature neuronal cell

β-Catenin normal expression Poorly differentiated neuronal cell Undifferentiated neuronal cell β-Catenin over expression Existing neuronal cell

GCL

SGZ Migration Differentiation Synaptogenesis

Proliferation

Fig. 2. Model of neurogenesis affected by b-catenin in the adult hippocampal dentate gyrus. In the subgranular zone (SGZ) of the dentate gyrus, compared with stem cells normally expressed with b-catenin (sky blue), cells overexpressed with b-catenin (deep blue) promote the proliferation of themselves. The low expression of b-catenin in stem cells (light blue) inhibits its proliferation. In the layer (GCL), the migration of light blue low-expressed b-catenin reveals deficiency. In the following events, the differentiation of deep blue cells overexpressed b-catenin is inhibited, and in the stage of syanptogenesis, light blue cell low-expressed b-catenin reveals deficiency in aspects of axonal and dendritic development.

ª 2010 The Authors. European Journal of Neuroscience ª 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1–8 4 L. Zhang et al. neurogenesis in vivo by way of injecting a single dose of BrdU into where they differentiate into neuronal cells of the granular layer and adult BATGAL mice. It was indicated that Wnt ⁄ b-catenin pathway extend axonal projections to the CA3 area of the Ammon’s horn activity was observed in BrdU-positive cells with morphological (Markakis & Gage, 1999). Newborn cells in the anterior part of the features of proliferating (Lie et al., 2005). By contrast, SVZ migrate through the rostro-migratory stream to the using a secreted mutant Wnt1 protein (dnWnt), which non-autono- (OB), where they differentiate into , granule and mously blocks Wnt signaling in vivo (Hoppler et al., 1996; Garcia- periglomerular (Lois & Alvarez-Buylla, 1994). Regarding Castro et al., 2002), Lie et al. (2005) found that blockade of Wnt the role of b-catenin in migration of precursor cells, Chenn & Walsh signaling reduces neurogenesis from adult hippocampal stem ⁄ progen- (2003) observed that adult transgenic mice, which expressed lower itor cells (AHPs) in vitro, and abolishes neurogenesis almost levels of b-catenin, indicated that the OBs of adult transgenic animals completely in vivo. In addition, Qu et al. (2010) took cell cycle are not increased in size relative to those of normal mice, suggesting analysis to reveal that the b-catenin activation promoted neural stem that the normal migratory behavior of these neurons may be impaired cell proliferation, resulting in an increase in cell population, which or misdirected. They concluded that the brains from adult transgenic further suggests that the b-catenin promotes neural prolif- mice that expressed lower levels of b-catenin in neural precursors eration and self-renewal. Furthermore, Qu et al. (2010) transduced the show an apparent arrest of migration. This suggests that b-catenin has b-catenin inhibitor Axin into the SVZ of adult wild-type brains, and been related to its role in migration of precursor cells. Unfortunately, detected decreased numbers of GFP+BrdU+ cells compared with that detailed and strong research has not been provided to demonstrate how in the control vector-transduced brains. These results all support the b-catenin plays a role in migration of precursor cells in adult concept that the effect of Wnt ⁄ b-catenin signaling plays a role in neurogenesis, but it is indicated that performance of further studies in promoting proliferation in adult brains. this field would be beneficial. This view has been specially demonstrated in the studies for Neuronal differentiation is controlled by both intrinsic and extrinsic proliferation of hippocampal progenitors. So far, the central impor- regulators (Inestrosa & Arenas, 2010). Regarding intrinsic regulators, tance of the Wnt ⁄ b-catenin signaling during development of the not surprisingly, the Wnt ⁄ b-catenin signaling pathway is important in hippocampus has been demonstrated. In the hippocampus, Machon regulating neural development but also appears to be involved in adult et al. (2003) observed with the D6-Cre ⁄ b-cateninflox ⁄ flox mutational neurogenesis (Malaterre et al., 2007). Apart from the Wnt ligands to mice and found that b-catenin-mediated Wnt signaling was central in regulate this process, b-catenin plays a role in neurogenesis. The controlling the expansion of the early progenitor pool in the activation of b-catenin leads to the proliferation of the neural developing hippocampus. Similarly, transgenic mice with the progenitor pool, resulting in the expansion of the entire D6-driven Dkk1 gene, which encodes extracellular negative protein (Chenn & Walsh, 2002). In addition, a GSK-3b inhibitor, which of Wnt ⁄ b-catenin pathway, exhibited reduced canonical Wnt signaling phosphorylates b-catenin, was found to induce the selective differen- in the cortex and hippocampus. As a result, inhibition of the canonical tiation of stem cells into neurons (Ding et al., 2003). By contrast, Wnt signaling by the ectopic expression of Dkk1 extends the cell cycle treatment with an inhibitor of GSK-3b was shown to inhibit the and reduces proliferation of neurogenic progenitor cells. Therefore, all differentiation of progenitor cells in the SVZ into neuroblasts (Adachi hippocampal fields were reduced in size (Solberg et al., 2008). et al., 2007). Other similar studies utilizing conditional knockout and Furthermore, they indicated that although Wnt ⁄ b-catenin signaling transgenic mice with overexpressed b-catenin have shown that could not be sufficiently inhibited in the adult DG of D6-Dkk1 mice, b-catenin plays an important role in neuronal progenitor proliferation the affected progenitor pool was not able to rebuild a normal size of and cell survival and differentiation (Zechner et al., 2003; the DG (Solberg et al., 2008). Recently, Eric et al. studied the Lee et al., 2004). Furthermore, analysis of whether precursors participation of Wnt ⁄ b-catenin in hippocampal neurogenesis. It was differentiated into neurons or remained as precursors after inhibition found that autonomous Wnt signaling is a conserved feature of the of b-catenin signaling has indicated that inhibition of b-catenin neurogenic niche that preserves the delicate balance between neural signaling increases the proportion of cells that exit the ventricular zone stem cell maintenance and differentiation (Wexler et al., 2009). and differentiate into neurons (Woodhead et al., 2006). Following Wexler et al. (2009) demonstrate that inhibition of the canonical Wnt those findings, it has been proposed that b-catenin may inhibit pathways depletes multipotent progenitors from the AHP population. neuronal differentiation in the process of adult neurogenesis. Unfor- tunately, it is still unclear how the stem cells with overexpressed b-catenin are inhibited to differentiate into mature neural cells, and the exact patterning of these inhibited cells is also unknown. Wnt ⁄ b-catenin signaling in the migration of precursor cells and the differentiation of neurons of the mammalian brain involves a complex series of precisely timed events that can be divided into four phases: Wnt ⁄ b-catenin signaling in (i) generation of precursor cells from stem cells; (ii) migration of Neurons are continuously added to the brain throughout life. These precursor cells to target brain regions; (iii) differentiation of new neurons develop dendritic arbors, set up functional connections with neurons into mature synaptically active cells; and (iv) pruning of new existing neurons, and integrate into neuronal circuitry. It is known that neurons by apoptosis. The discovery that these events continue into the components of Wnt signaling in early stages of neural develop- adulthood in discrete regions of the adult brain of rats (Altman & Das, ment have been linked to their role in neurite patterning and in 1965) and humans (Eriksson et al., 1998) overthrew the dogma of a synaptogenesis; furthermore, the appearance of these components in fixed neuronal complement at birth or soon after (Toro & Deakin, the mature nervous system suggests a role of this pathway in synaptic 2007). So, it is significant that we discuss adult neurogenesis and the and functional maintenance. It is noteworthy that b-catenin, as a most aspects of migration and differentiation in mammalian brain. crucial component in this pathway, may also perform some functions It is well known that neurogenesis occurs primarily in two areas of in synapse. the mammalian brain, the SGZ and the SVZ. In the DG, newly In axonal development, b-catenin participates in axonal localization generated precursor cells in the SGZ migrate to the granular layer of presynaptic proteins (Bamji et al., 2003) in early and late

ª 2010 The Authors. European Journal of Neuroscience ª 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1–8 The Wnt ⁄ b-catenin signaling pathway 5 development. Many studies show that mutant embryos for Wnt and there is evidence that shows that Ab-dependent neurotoxicity signaling components, such as b-catenin, perform defects in the induces a loss of function of Wnt signaling components (De Ferrari precise projection of the axonal growth cone within the nerve cord et al., 2003; Alvarez-Buylla & Lim, 2004; Fuentealba et al., 2004). (Loureiro & Peifer, 1998; Yoshikawa et al., 2003; Sato et al., 2006; In primary cultures of hippocampal and cortical neurons exposed to Bhat et al., 2007). In vitro experiments with cultures of cerebellar Ab neurotoxicity, an increased activation of GSK-3b, the hyper- granule neurons show that an inhibition of GSK-3b with lithium phosphorylation of tau proteins, together with the loss of the induce axonal spreading and branching by the remodeling of axonal network have all been observed (Busciglio et al., 1995; (Lucas & Salinas, 1997; Hall et al., 2000). In dendritic Takashima et al., 1998). Exposure of neurons in culture to Ab development, there are studies that have shown that b-catenin is induces apoptosis and promotes tau hyperphosphorylation, through critical for dendritic morphogenesis (Yu & Malenka, 2003); in GSK-3b activity (Toledo et al., 2008). In contrast, Toledo et al. fact, increasing the levels of neuronal b-catenin improves the (2008) studied the relationship between Ab-induced neurotoxicity dendritic arborization without requiring gene transcription mediated and lower cytoplasmatic levels of b-catenin in early years, showing by Wnt ⁄ b-catenin. Neuronal activity participates in dendritic arbor- that inhibition of GSK-3b by lithium protects rat neurons from ization (Lohmann et al., 2002), with the requirement of b-catenin. Gao Ab-induced damage. More recently, it was found that the upregu- et al. (2007) show that specific knockout of b-catenin in newborn lation of b-catenin during tau hyperphosphorylation prevents the cell neurons, without affecting b-catenin expression in neural progenitor from going into apoptosis. Moreover, the knockdown of b-catenin cells, led to defects in dendritic morphology of these newborn neurons produces an increase in the numbers of apoptotic cells; and also in vivo, and that the majority of newborn neurons that cannot extend antagonizes the anti-apoptotic effects of tau (Li et al., 2007). In dendrites survive < 1 month after they were born. Moreover, in addition, a loss of Wnt signaling through the b-catenin–TCF mammals, depolarization induces dendritogenesis, which requires Wnt pathway increases neuronal vulnerability to apoptosis induced by Ab and b-catenin release (Yu & Malenka, 2003). The above results (Zhang et al., 1998), and possible defects in Wnt signaling could indicate that b-catenin participates in dendritic development of contribute to the pathogenesis of AD (De Ferrari & Inestrosa, 2000; postnatal-born neurons, and therefore it is essential for neurogenesis Mudher & Lovestone, 2002; Caricasole et al., 2003). However, in the postnatal brain. b-catenin transfection led to restoration of neurogenesis (He & Shen, Regarding the function of b-catenin in synaptic assembly, some 2009). In AD, it has been demonstrated that neurotoxicity of Ab in studies show that the mechanism involved in presynaptic assembly is neurons is linked to increased levels of GSK-3b and loss of transcription independent. In cultured neurons, Wnt signaling b-catenin, and that b-catenin is required for human restoration of increases the number and size of synaptic vesicle proteins without injured brain. affecting presynaptic protein expression, before stabilization of Impaired Wnt ⁄ b-catenin signaling has also been observed in b-catenin and its translocation into the nucleus (Cerpa et al., 2008). cellular models of HD (Carmichael et al., 2002). b-Catenin levels In vivo, Wnt deficiency also affects the localization of presynaptic and impairment of TCF-mediated transcription have been observed in proteins without affecting their levels (Ahmad-Annuar et al., 2006). HD mutation, and overexpression of b-catenin results in protection Similarly, it was observed in conditional mutant mice for b-catenin against the HD mutation (Caricasole et al., 2005). that this protein is required for the proper localization of synaptic In summation, the role of b-catenin has been described in aspects of vesicles along the , but through a mechanism independent of neurodegenerative disease, and a restoration of normal Wnt ⁄ b-catenin TCF-mediated transcription (Bamji et al., 2003). In addition, the activity has also been shown to protect against neurodegeneration in presynaptic clustering of a7-nAChR induced by Wnt-7a depends on cellular disease models. APC but is independent of b-catenin stabilization (Farias et al., 2007). These findings suggest that b-catenin may not be crucial in the stage of synaptic assembly, which is transcription independent. Conclusions Great progress has already been made in deciphering the character- istics of b-catenin and the network of Wnt ⁄ b-catenin signaling The Wnt ⁄ b-catenin signaling pathway in neuronal pathways by a number of researches. In recent years, adult neurogen- degeneration diseases esis has become one of the most rapidly growing areas in neuroscience Studies on neurodegenerative diseases in humans indicate that research. It is interesting to find the relationship between the Wnt ⁄ b-catenin signaling is altered or involved in the pathophysiology Wnt ⁄ b-catenin signaling pathway and adult neurogenesis. In the of these diseases, such as AD and Huntington’s disease (HD), and is adult brain, stabilized b-catenin modulates the proliferation of neural directly related to neurogenesis. stem cells, induces newly generated neuronal cells migration into In patients with AD, active GSK-3b has been found in brains staged relevant regions accurately, and then mediates them to differentiate to for AD neurofibrillary changes (Pei et al., 1999). Consequently, a mature neurons and ultimately plays a role in synaptogenesis. In decrease in b-catenin levels and an increase in tau hyperphosphory- particular, in the process of adult neurogenesis, increased b-catenin lation have been revealed in AD. Also, neurodegeneration and spatial promotes stem cells proliferation and inhibits the differentiation of deficits have been observed in GSK-3b conditional transgenic new neurons, which is attractive for the research and treatment of mice (Lucas et al., 2001; Hernandez et al., 2002). Furthermore, neuronal degeneration and oncology in the CNS. Although plenty studies show that familial AD-linked PS proteins form multiprotein of evidence has been provided in this field, much remains to be complexes with the cell adhesion ⁄ Wnt signaling b-catenin protein investigated with regard to other fundamental biological functions and a-catenin and GSK-3b (Toledo et al., 2008). the interactive effects of Wnt signaling with other signaling networks Alzheimer’s disease is characterized by the accumulation of the in the adult brain. Further work is necessary to elucidate the exact amyloid-b-peptide (Ab), which is believed to induce apoptosis in molecular mechanisms of biological effects of Wnt ⁄ b-catenin signal- newly generated neurons (He & Shen, 2009) and have a key ing, in order to provide some basic methods toward treatments for function in the cognitive deficits observed in AD (Selkoe, 2001), neurodegeneration diseases and tumors in the CNS.

ª 2010 The Authors. European Journal of Neuroscience ª 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1–8 6 L. Zhang et al.

Acknowledgements Carmichael, J., Sugars, K.L., Bao, Y.P. & Rubinsztein, D.C. (2002) Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity We thank Linchun Huan, Wangmiao Zhao, Qi Zhang and Rong Yan for helpful caused by the Huntington’s disease mutation. J. Biol. Chem., 277, 33791– comments on the manuscript. Research in the authors’ laboratory is supported 33798. by the National Natural Science Foundation of China No. 30973090 and Cerpa, W., Godoy, J.A., Alfaro, I., Farias, G.G., Metcalfe, M.J., Fuentealba, R., Natural Science Foundation of Tianjin No. 09JCZDJC17200. Bonansco, C. & Inestrosa, N.C. (2008) Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J. Biol. Chem., 283, 5918–5927. Abbreviations Chen, R.H., Ding, W.V. & McCormick, F. (2000) Wnt signaling to beta-catenin involves two interactive components. 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