\r\n\tMain types of important health problems that occur in humans are: Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, Loa loa, Mansonella ozzardi, Dipetolonema perstans, Dipetolonema streptocerca, Dirofilaria repens, Dirofilaria tenuis, Dirofilaria immitis, and Dracunculu smedinensis. \r\n\tEpidemiologically Filarisis is estimated to be prevalent in more than 120 million people worldwide. Mostly it is prevalent in hot and humid subtropical regions. Countries where filariasis may be found in Asia: Amman, China, India, Japan, Korea, Vietnam, Indonesia, Ceylon, Malaysia and Thailand; in the Mediterranean region: Spain, Italy, Macedonia; in Africa: (between 150 North and 130 South parallels) Angola, Tanzania, Ghana, Morocco, Algeria, Tunis, Egypt; and in Central America: Mexico, Honduras, Venezuela, Caribbean, Guyana. \r\n\tClinical manifestation may vary from painful inflammatory swellings of lymph nodes in acute infections to lymphedema due to blockage of lymphatic system in chronic cases. The diagnosis firstly depends on the “suggestive symptoms”. Blood tests such as Indirect Hemaglutination (IHA), Enzym-Linked Immunosorbent Assay (ELISA) are indirect diagnostic tests and PCR. Definitive diagnosis depends on direct identification of microfilariae in blood samples or involved-tissue biopsies. The treatment of choice in Filariasis is a combined regimen of diethylcarbamazine (DEC) 6 mg/kg, ivermectin 150 mg/kg and albendazole (ALB) 400 mg single-administration. Prevention: Treatment of patients with filariasis and vector control is possible
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ae0039d441f0aea87a81d27d582721e1",bookSignature:"Prof. Tonay Inceboz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9112.jpg",keywords:"ilariasis, morphology, vector, geographic distribution, Lymphatic system, Wuchereria bancrofti, Brugia malayi, Brugia timori, Cutaneous and ocular system, Dipetolonema streptocerca, Loa loa, Onchocerca volvulus, Serous cavity, Mansonella perstans and Mansonella ozzardi, Dirofilaria immitis, Other filariae, Dipetolonema perstans, Dipetolonema streptocerca, Dracunculus medinensis, microscopy, serology, molecular, drugs, prevention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 10th 2019",dateEndSecondStepPublish:"October 1st 2019",dateEndThirdStepPublish:"November 30th 2019",dateEndFourthStepPublish:"February 18th 2020",dateEndFifthStepPublish:"April 18th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. 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\n\t\t\t
1. Introduction
Wnts compromise a large family of secreted glycoproteins that have shown to be part of the signaling molecules that regulate several aspects of development such as axis formation and midbrain development [1, 2]. In mammals at least 19 Wnt members have been found. The interaction of a Wnt protein with members of the Frizzled (Fz) family of seven-pass transmembrane cell-surface receptors triggers the activation of the Wnt signaling pathway [3-5]. In human and mice, 10 members of the Fz family have been identified. In addition, receptor-like tyrosine kinase (Ryk) and receptor tyrosine kinase-like orphan receptor (Ror2) have been identified as alternative Wnt receptors [6-8]. Different Wnt signaling cascades are activated downstream the Wnt receptors, identified as Wnt/β-catenin or canonical pathway, and β-catenin-independent or non-canonical pathways. The canonical pathway involves the transcription of Wnt target genes, while activation of non-canonical Wnt pathways may induce either an increase in intracellular calcium concentration or activation of the c-Jun-N-terminal kinase (JNK) cascade [3, 9, 10].
The Wnt pathway participates in the development of the central nervous system (CNS) and growing evidence indicate that Wnts also regulates the function of the adult nervous system [11, 12]. In fact, most of the key components including Wnts and Fz receptors are expressed in the adult brain [13, 14]. Wnt ligands have shown to regulate synaptic assembly as well synaptic plasticity and neurotransmission [15-20], and more recently it has also been involved in the adult neurogenesis [21-25].
Deregulation of the Wnt signaling has been associated to several pathologies, been cancer the most widely documented [26-28]. More recently, altered Wnt signaling have been related to mental disorders, mood disorders and neurodegenerative diseases [12, 29-32].
In the first part of this chapter we will address what is currently known about the signaling cascades of canonical and non-canonical pathways. Then, we will review recent findings from our and other labs on the specific effects of different Wnt ligands on the structure of pre- and postsynaptic regions and on glutamatergic neurotransmission in hippocampal neurons. The synaptic role of some Fz receptors will also be reviewed. Finally, the neuroprotective effect of the Wnt signaling activation will be discussed mainly focused on the protection against the toxicity of Aβ-peptide aggregates associated to the pathogenesis of Alzheimer’s disease.
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2. The Wnt signaling pathway: Canonical and non–canonical signaling cascades
The binding of Wnt ligands to Fz receptors can trigger the activation of different signaling cascades. In addition to Fz, other proteins have been described as alternative receptors or co-receptors, such as the low-density lipoprotein receptor-related protein 5 (LRP5), LRP6, Ror1, Ror2 and Ryk [3, 33-36], increasing the complexity of the Wnt signaling activation. It has been suggested that the binding of Wnts to specific receptors/co-receptors may selectively activate distinct signaling pathways.
The first Wnt signaling pathway identified was the canonical Wnt/β-catenin pathway (Figure 1). In the absence of Wnt stimulation, the levels of cytoplasmic β-catenin are low since it is ubiquitinated and constantly degraded in the proteasome [37]. β-catenin is phosphorylated by casein kinase 1α (CK1α) and glycogen synthase kinase-3β (GSK-3β) in a multiprotein complex composed also of the scaffold protein axin and adenomatous polyposis coli (APC) [38-42]. Phosphorylated β-catenin is recognized by β-TrCP, which is part of an E3 ubiquitin ligase complex, and is ubiquitinated and subsequently degraded [43]. Activation of the Wnt/β-catenin pathway initiated by the binding of a Wnt ligand to a Fz receptor and coreceptors LRP5/6 activates the protein Dishevelled (Dvl) usually by phosphorylation, and triggers the recruitment of axin to the phosphorylated tail of LRP, inhibiting the degradation pathway consequently inducing the cytoplasmic stabilization of β-catenin which enters the nucleus and regulates the transcription of Wnt target genes [28]. Recently, it was shown that when the destruction complex is associated with phosphorylated LRP, it may still capture and phosphorylates β-catenin, but ubiquitination is blocked (Figure 1, right panel) [44].
In the nucleus, β-catenin binds to members of the family of T-cell factor (Tcf) and lymphoid enhancer factor (Lef) [45-47]; this binding displaces Groucho, which is bound to Tcf/Lef and recruits histone deacetylases (HDAC) to repress the transcription of Wnt target genes [48-51]. Several Wnt target genes have been identified including c-Myc, cyclin D1, Axin2, Calcium/calmodulin-dependent protein kinase type IV (CamKIV) [52-55]. In addition, by using an in silico analysis based on multiple Classification and Regression Tree (CART), 89 new genes were predicted to be targets of the Wnt/β-catenin pathway [56].
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Figure 1.
\n\t\t\t\t\t\tCanonical Wnt/β-catenin signaling pathway. (Left panel) In the absence of a Wnt protein, GSK-3β phosphorylates β-catenin which targets it for ubiquitination by β-TrCP and degradation in the proteasome. (Right panel) Activation of the signaling pathway by the binding of a Wnt ligand to Fz receptor and coreceptors LRP5/6 triggers the association of the destruction complex with phosphorylated LRP. In this condition, the complex may still capture and phosphorylate β-catenin, however the ubiquitination is blocked and it is stabilized in the cytoplasm and enters the nucleus to regulate the transcription of Wnt target genes.
There are at least two β-catenin-independent pathways: the planar cell polarity (PCP) pathway and the Ca2+ pathway (Figure 2). The PCP pathway was originally identified in Drosophila where it regulates tissue polarity and cell migration [10, 57]. This signaling pathway requires Fz receptors and Dvl and activates small GTPases including Rho and Rac and the protein kinase JNK. This pathway is also known as the Wnt/JNK pathway. The activation of the Wnt/Ca2+ pathway triggers the increase in intracellular Ca2+ levels and activates the protein kinases CamKII and protein kinase C (PKC) [10, 58]. It has been suggested that Wnt-mediated Ca2+ release involves heterotrimeric G proteins since it is inhibited by pertussis toxin [59]. As mentioned 10 Fz receptors are known in mammals. Fz receptors are seven-transmembrane-spanning receptors that belong to the G protein-coupled receptor (GPCR) list as a separate class [60]. Fz receptors have an extracellular amino-terminal region that contains a cysteine-rich domain (CRD) consisting of 120 to 125 residues with 10 conserved cysteines that is relevant for the binding of Wnt proteins [61]. Growing evidence indicate the involvement of G protein in the Wnt/Fz signaling. The first evidence came from inhibition of non-canonical Wnt effects by pertussis toxin [62]. Later on, many reports have indicated that heterotrimeric G protein participates of canonical and non-canonical Wnt signaling in Drosophila, Xenopus and mammals [63-69].
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Figure 2.
\n\t\t\t\t\t\tβ-catenin-independent Wnt signaling pathways. In the Wnt/JNK pathway or PCP pathway, a Wnt ligand through a Fz receptors and Dvl activates small GTPases including Rho and Rac and JNK, which in turns modulate cytoskeletal organization. The activation of the Wnt/Ca2+ pathway triggers an increase in intracellular Ca2+ levels which activates CamKII and PKC.
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3. Roles of the Wnt signaling pathway at central synapses
The Wnt signaling pathway has different roles during development linked to neurite patterning and synaptogenesis. Different Wnt ligands have been linked to the presynaptic assembly. In 1997, Salinas and co-workers demonstrated in cerebellar neurons that Wnt-7a increases the levels of synapsin I, a protein associated to synaptic vesicles [70]. Moreover, Wnt-7a mutant mice show a delay in the accumulation of synapsin I [71]. In hippocampal neurons Wnt-7a as well as Wnt-3a and Wnt-7b increases the number of pre-synaptic puncta suggesting a role for these ligands in presynaptic assembly [18, 72, 73]. In addition, Wnt-7a was found to stimulate recycling and endocytosis of synaptic vesicles using FM dyes [74]. In hippocampal neurons, Wnt-7a was also able to increase the expression as well as the clustering of the α7- nicotinic acetylcholine receptor (α7-nAChR), indicating that the Wnt signaling regulates the clustering of presynaptic receptors [75]. Interestingly, all these ligands are able to modulate presynaptic differentiation by activation of the Wnt/β-catenin signaling pathway, suggesting that some of the components associated with this pathway may be involved in the presynaptic effect. On the other hand, the non-canonical ligand Wnt-5a decreases the number of presynaptic terminals [72], indicating that canonical and non-canonical signaling pathways may have promoting and inhibitory effects on presynaptic differentiation respectively. In accordance, electrophysiological recordings on adult rat hippocampal slices showed that Wnt-7a, but not Wnt-5a, increased neurotransmitter release in CA3-CA1 synapses by decreasing paired pulse facilitation and increasing the frequency of miniature excitatory postsynaptic currents (mEPSC) [73]. Also, Wnt-7a/Dvl1 double mutant mice exhibit decreased mEPSC frequency at the mossy fiber-granule cell synapse revealing a defect in neurotransmitter release [18].
The Wnt signaling also plays relevant roles in the postsynaptic structure. Wnt-5a, which activates non-canonical Wnt signaling cascades in hippocampal neurons [19, 76], modulates postsynaptic assembly by increasing the clustering of the postsynaptic density protein-95 (PSD-95) and increases spine morphogenesis in cultured hippocampal neurons [15, 19]. PSD-95 is a scaffold protein of the postsynaptic density (PSD), which is a multiprotein complex that interacts with key molecules involved in the regulation of glutamate receptor targeting and trafficking and regulatory proteins relevant for neurotransmission [77, 78]. In hippocampal neurons, Wnt-5a induces a fast increase in the number of clusters of PSD-95 without affecting total levels of PSD-95 protein or presynaptic protein clustering [19]. This postsynaptic effect is dependent on Wnt/JNK signaling pathway as demonstrated by using JNK inhibitors. In long-term experiments, we observed that Wnt-5a is also able to increase the total number of synapses [79]. When hippocampal neurons were incubated with the formylated hexapeptide Foxy-5, which is derived from the sequence of Wnt-5a and mimics the full Wnt-5a molecule action in neurons and other systems [19, 80], there was an increase in PSD-95 since 1 hour, but after 24 hours an increase in the synaptic vesicle protein 2 (SV2) clustering was also observed. In consequence, there was an increase in the total number of synaptic contacts [79].
Also, we determined that Wnt-5a induced a transient formation of dendrite protrusions that resulted in a net increase of mature dendrite spines. Videomicroscopy revealed that Wnt-5a induced de novo formation of dendritic spines and also increased the size of the preexisting ones [15]. Interestingly, treatment with the soluble CRD region of Fz2, acting as a Wnt scavenger, decreased spine density in cultured neurons, supporting the physiological relevance of this finding and supporting the implication of Wnt ligands in dendrite spine morphogenesis. Wnt-7a is also able to increase the density and maturity of dendritic spines through a CamKII-dependent mechanism [81]. Wnt-7a rapidly activates CaMKII in spines and inhibition of this kinase abolishes the effects of Wnt-7a on spine growth and excitatory synaptic strength. This finding implicates the Wnt/Ca2+ signaling cascade in synaptic effects of Wnt ligands. Interestingly, Wnt-5a and Wnt-7a induces an increase in intracellular Ca2+ concentration [15, 81], supporting the activation of this non-canonical Wnt pathway.
In addition to the structural effects of Wnt ligands at the excitatory synapse, different Wnts have shown modulatory effects on glutamatergic neurotransmission. Wnt-3a modulates the recycling of synaptic vesicles in hippocampal synapses [73, 82] and is able to induce an increase in the frequency of mEPSC [20]. In hippocampal slices, blockade of Wnt signaling impairs long-term potentiation (LTP), whereas activation of Wnt signaling facilitates LTP [17]. In the case of Wnt-5a, acute application of this ligand in hippocampal slices increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and upregulates synaptic NMDA receptor currents facilitating induction of LTP [15, 16]. Interestingly, Wnt-5a produced a two-step increase in the amplitude of NMDAR responses [16]. The mechanisms involved in this two-step effect of Wnt-5a were investigated by the delivery of specific protein kinase inhibitors via the recording pipette. Specifically, the role of PKC and JNK was investigated, since these are two known downstream kinases of the non-canonical pathway. Inhibition of Ca22+-dependent PKC isoforms with Go6976 or the more general PKC inhibitor calphostin C eliminated the first step of potentiation of NMDAR currents and did not affect the second one. On the contrary, the slower developing increase in NMDAR currents was blocked by the JNK inhibitors TI-JIP153-163 and SP600125. This indicate that there are two mechanisms involved in in the potentiation of NMDAR by Wnt-5a. There is a fast PKC-dependent potentiation and a slower JNK-dependent potentiation that does not require previous activation of PKC [16].
Wnt-5a also regulates postsynaptically the hippocampal inhibitory synapses [76]. Wnt-5a induces surface expression and maintenance of GABAA receptor in the membrane of hippocampal neurons, increases the amplitude of GABA-currents due to a postsynaptic mechanisms, and induces the recycling of functional GABAA receptors through activation of CaMKII [76]. Therefore Wnt-5a is able to modulate both, excitatory and inhibitory synapses which must be relevant for neurotransmission.
The novel role for Wnt ligands in synaptic transmission provides a mechanism for Wnt signaling to acutely modulate synaptic plasticity and brain function in later stages of development and in the mature organism. Importantly, neuronal activity modulates the release and expression of Wnt ligands which may be relevant for the function of these ligands during neurotransmission. Activation of NMDA receptors increases the expression of Wnt-2 in hippocampal neurons which then stimulates dendritic arborization [83]. On the other hand, tetanic stimulation induce NMDA receptor-dependent synaptic Wnt3a release [17]. The role for endogenous Wnts was supported by incubation of hippocampal slices with secreted Wnt inhibitors, such as secreted Frizzled-related protein-2 (sFRP-2), which showed that endogenous Wnt ligands are modulators of glutamatergic neurotransmission being necessary to maintain basal NMDA receptor synaptic transmission [15, 16].
The in vivo relevance for the role of Wnt signaling in activity-mediated synaptic connectivity was revealed in mice exposed to an enriched environment (EE). These animals showed increased complexity and number of large mossy fiber terminals in the CA3 region [84]. EE increased Wnt7a/b levels in CA3 pyramidal neurons and inhibiting Wnt signaling through locally applied sFRP-1, suppressed the effects of EE on synapse numbers and further reduced synapse numbers in control mice.
These findings show that Wnt ligands are important regulators of the synaptic structure during development and in adult neurons, and that the Wnt pathway is one of the signaling cascades regulated by neuronal activity that is involved in the regulation of neurotransmission in adult nervous system.
In addition to the role of Wnts, Fz receptor have also been involved in synaptic structure and function. In the hippocampus, we have determined that different Fz receptors have very different patterns of expression during development, being some of them highly expressed in adulthood and others during early development [85]. In addition, the distribution of Fzs in hippocampal neurons is also very specific. Some receptors, are located in the synaptic region, while others are mainly located in the soma or in the growth cones of young neurons [85]. These findings suggest that these receptors could be important regulators for the specific activation of the Wnt signaling cascades during the development of hippocampal circuits. In fact, we determined an association of the distribution with specific functions. In hippocampal neurons, Fz1 is located in the synaptic region co-localizing with presynaptic proteins and with active synaptic vesicle recycling sites [82]. Interestingly, overexpression of Fz1 increased the number of clusters of Bassoon, a component of the active zone involved in the structural organization of neurotransmitter release sites that is recruited early during synapse formation [86], suggesting that Fz1 regulates synaptic differentiation. In agreement, treatment with the extracellular CRD of Fz1 decreased Bassoon clustering which was not observed with the CRD of Fz2, indicating a receptor specificity for the synaptic effect [82]. Fz5 also has a role in mature neurons where it modulates the synaptogenic effect of Wnt7a [87]. As well as Fz1, Fz5 is present in synaptosomes and colocalizes with synaptic markers, and changes in the expression of this receptor modulates the density of synaptic sites [87]. In addition to its function in mature neurons, Fz5 was shown to be in high levels in the growth cones of developing hippocampal neurons [85], and we have recently determined that this receptor is involved in neural polarization (unpublished results). We determined that overexpression of Fz5 triggers a mislocalization of axonal proteins such as Tau-1 and phosphorylated MAP1B (MAP1BP), which change their distribution to the whole cell suggesting altered polarization. When the expression of Fz5 is knocked-down by shRNA, MAP1BP is not polarized and is almost completely lost. These findings suggest that in developing hippocampal neurons Fz5 is relevant for neural polarization. These studies indicate that Fz receptors are relevant players in both the developing and the adult nervous system and support the notion that the Wnt signaling pathway is crucial for different aspects of the development and function of the CNS.
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4. Role of Wnt signaling in adult neurogenesis
In the adult brain, there are two regions where there is a continuous generation of new neurons (Figure 3A), the subventricular zone (SVZ) of the lateral ventricles [88] and the subgranular zone (SGZ) in the hippocampal dentate gyrus [89]. In the SVZ, astrocyte-like neural stem cells (NSCs), called type B1 cells, generate type C cells that rapidly proliferate and give rise to type A neuroblasts (Figure 3B). These cells migrate through the rostral migratory stream to the olfactory bulb where they became interneurons [88] (Figure 3A). In the SGZ, radial and non-radial neural precursor cells give rise to transient amplifying progenitors that generate neuroblasts and then became immature neurons that extend dendrites toward the molecular layer and project their axons through the hilus toward the CA3 region [90] (Figure 3C). Newborn neurons then mature and fully integrate into the preexisting hippocampal circuitry.
Adult neurogenesis is highly regulated by intrinsic and extrinsic mechanisms. Many signaling pathways have been identified as regulators of different aspects of neurogenesis. Notch, Shh, BMPs, and Wnts are part of the signaling molecules of the niche that regulate the maintenance, activation and fate specification of neural precursor cells [91, 92].
In Wnt/β-catenin reporter mice (BATGAL) it was shown that this pathway is active in the SGZ and the dentate granule cell layer [23]. In that study, authors determined that Wnt3 is expressed in adult hippocampal astrocytes and that adult hippocampal progenitor (AHP) cells express key components of the Wnt/β-catenin signaling pathway. These findings suggested that the Wnt pathway may be involved in the regulation of adult neurogenesis. In vitro analysis in cultured cells revealed that Wnts derived from hippocampal astrocytes stimulate Wnt/β-catenin signaling in isolated AHPs inducing their neuronal commitment [23]. The effect of the Wnt signaling was supported in vivo using lentiviral vectors expressing Wnt3a or a secreted mutant Wnt1 protein that blocks Wnt signaling. Lentiviruses were stereotactically injected into the dentate gyrus of rats. As assessed by the incorporation of the nucleotide analog BrdU and immunodetection of the immature neuron protein doublecortin (DCX), blocking the Wnt signaling decreases adult hippocampal neurogenesis while stimulating this pathway has the opposite effect [23]. More recently, and by using the same lentiviral approach to block Wnt signaling in the dentate gyrus of adult rats it was shown that Wnt-mediated adult hippocampal neurogenesis contributes to learning and memory [93]. In the SVZ, β-catenin signaling also plays a role in the proliferation of progenitor cells in the adult mouse brain [94]. Retrovirus-mediated expression of a stabilized β-catenin promoted the proliferation of type C cells and inhibited their differentiation into neuroblasts. Also in the SVZ, transduction of the β-catenin inhibitor axin by intracranial lentiviral delivery decreased cell proliferation as revealed by decreased BrdU labeling [95], further supporting a role for Wnt/β-catenin signaling in neural stem cell proliferation in the neurogenic areas of adult brain.
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Figure 3.
\n\t\t\t\t\t\tNeurogenesis in the adult brain. (A) Schematic representation of adult rodent brain highlighting the two neurogenic regions. The hippocampus and the SVZ (boxed). (B) Schematic of the SVZ in the wall of the lateral ventricles. Distinct stem/progenitor cell types (types B, C, and A) are shown. (C) Neurogenesis in the SGZ of the hippocampal dentate gyrus. The progression of radial type 1 cells to mature newborn granule neurons is schematized.
The Wnt-mediated effects in neurogenesis may be caused by the transcriptional activation of NeuroD1 which is dependent on the Wnt/β-catenin signaling activation [25]. NeuroD1 is a basic helix-loop-helix transcription factor important for the generation of granule cell and olfactory neuron in the embryonic and adult brain [96]. NeuroD1 gene promoter has overlapping DNA-binding site for Sox2 and TCF/LEF, then the activation of this gene implies activation of the canonical Wnt pathway and removal of Sox2 repression from the NeuroD1 gene promoter [25]. More recently, Prox1 was also determined as a target of the Wnt/β-catenin pathway relevant for neurogenesis [22]. Prox1 is expressed in newborn and mature granule cells and is required for the proper differentiation and survival of newborn granule cells, but not for the maintenance of granule cells after they have fully matured [22].
In addition, Wnts could indirectly modulate adult neurogenesis thorough their effects on neuronal activity. As previously described, different Wnts regulate glutamatergic neurotransmission, and evidence indicates that neural progenitor cells respond to neuronal activity as part of their differentiation program [97]. GABA is an important modulator of adult hippocampal neurogenesis being critical for the proper development and maturation of adult-born neurons [98-100]. Interestingly, Wnt-5a through activation of CaMKII, induces the recycling of functional GABAA receptors on hippocampal neurons and modulates inhibitory synapses [76].
As mentioned, in neurogenic niches Wnts are provided by astrocytes [23], and during aging it was reported that the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes declines [101], which may be one of the factors underlying the impairment of neurogenesis that is observed in aging [102, 103]. On the contrary, running, that is a potent stimulator of adult neurogenesis in the SGZ [104] was found to significantly increase de novo expression of Wnt-3 [101], pointing to the Wnt pathway as one of the factors involved in running-mediated increase in neurogenesis. In addition to astrocytes-derived Wnts, an autocrine Wnt signaling activity has been observed in adult hippocampal progenitors (AHPs) derived from adult rat brains. Inhibiting this autocrine Wnt signaling increases the number of neurons formed and leads to a loss of multipotency among AHPs indicating that this autocrine pathway may preserve the balance between neural stem cell maintenance and differentiation [105].
The Wnt signaling has also been involved in the mechanism of the orphan nuclear receptor TLX (also known as NR2E1), which is an important regulator of neural stem cell maintenance and self-renewal in embryonic and adult brains [106, 107] and is involved in neurogenesis in the SVZ [108] and hippocampus [109]. To stimulate neural stem cell proliferation and self-renewal TLX activates the Wnt/β-catenin pathway in adult mouse neural stem cells by activating the expression of Wnt-7a, which expression was found to be downregulated in TLX-null mice, through binding to two TLX binding sites present in the Wnt-7a gene promoter [95]. Wnt-7a is important for adult neural stem cell proliferation in vivo since there is a decreased BrdU labeling in the SGZ and SVZ of adult Wnt7a knockout mice. In TLX-/- mice, intracranial lentiviral transduction of active β-catenin led to a considerable rescue of cell proliferation in the SVZ, suggesting that Wnt/β-catenin acts downstream of TLX to regulate neural stem cell proliferation in vivo [95].
It has been shown that low oxygen is associated with increased levels of β-catenin in vivo, and that hypoxia inducible factor-1α (HIF-1α) modulates the Wnt/β-catenin signaling in embryonic stem cells exposed to low oxygen [110]. Recently, we determined in vivo that hypoxia stimulates the activation of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice (our unpublished results), and stimulates cell proliferation in the SGZ of 2 month old wild-type mice.
Altogether, these findings indicate that the Wnt pathway is relevant not only for the development of the nervous system but also for the development of new neurons in the adult brain, being important for the maintenance and self-renewal of the stem cell pool and for the commitment and proliferation of new neurons.
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5. Wnt signaling in Alzheimer’s disease
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, cerebral accumulation of extracellular amyloid plaques composed mainly of amyloid-β peptide (Aβ), and synaptic alterations [111]. In addition to the accumulation of Aβ aggregates, which is a product of the processing of the amyloid precursor protein (APP), cytoskeletal alterations associated to the abnormal phosphorylation of the microtubule associated protein tau [112, 113] are early manifestations that lead to aberrant remodeling of dendrites and axons, the appearance of dystrophic neurites, synaptic loss [114], and eventually progressive loss of neuronal populations [112].
During more than a decade, a strong relationship between an impaired Wnt signaling pathway activity and neuronal damage in AD has been raised [31, 115-118]. Different studies have shown that Wnt signaling components are altered in AD [119-124], and in addition, the Wnt signaling pathway has been related to other neurodegenerative disorders such as autism and schizophrenia [30, 125]. Among the Wnt components that are affected in AD, it was shown that β-catenin levels are reduced in AD patients carrying presenilin-1 (PS-1)-inherited mutations [124], while the secreted Wnt antagonist Dickkopf-1 (Dkk1) is elevated in postmortem AD brains and brains from transgenic mouse models for AD [121, 126]. A variant of the LRP6 has been associated with late-onset AD, which confers low levels of Wnt signaling [119]. In addition, genetic studies show a link between Wnt signaling and AD. Epidemiological data show an increased risk for AD in populations where the allele 4 of apo-lipoprotein E (apoE4) is present. Interestingly apoE4 causes inhibition of the canonical Wnt signaling in PC12 cells upon stimulation with Wnt-7a as determined by luciferase activities and nuclear β-catenin levels [127]. Aβ directly binds to the extracellular CRD of Fz5 at or in close proximity to the Wnt-binding site inhibiting the canonical Wnt signaling pathway [128], linking directly Aβ to Wnt impairment. Moreover, the exposure of cultured rat hippocampal neurons to Aβ results in inhibition of canonical Wnt signaling as determined by destabilization of endogenous levels of β-catenin, increase in GSK-3β activity, and a decrease in the expression of some Wnt target genes [129]. Moreover, acute exposure to Aβ increases Dkk1 mRNA levels in hippocampal brain slices, which seems to be associated to synaptic loss induced by Aβ [130].
As mentioned, one of the hallmarks of AD brains is the abnormal phosphorylation of the tau protein which accumulates as intraneuronal neurofibrillary tangles [131]. Several kinases can phosphorylate tau in vitro; however, the bulk of the information supports that Cdk5, extracellular signal-related kinase 2, microtubule affinity-regulating kinase and GSK-3β, a key component of the Wnt cascade, are the most relevant kinases for tau phosphorylation in vivo [132, 133]. Cultured neurons exposed to Aβ show an increased GSK-3β activity [134, 135], and active GSK-3β has been found in brains staged for AD neurofibrillary changes, with a concomitant decrease in β-catenin levels and an increase in tau hyperphosphorylation [136]. Also, neurodegeneration and spatial learning deficits have been observed in GSK-3β conditional transgenic mice [137, 138]. Interestingly, a study shows that the phosphorylation of tau antagonizes apoptosis by stabilizing β-catenin; therefore, up-regulation of β-catenin during tau phosphorylation prevents the cell from going into apoptosis. Increasing levels of phosphorylated tau was correlated with increased levels of nuclear β-catenin, and the knockdown of β-catenin antagonizes the anti-apoptotic effects of tau [139]. These findings support a role of β-catenin as a survival element in AD.
Several studies have shown neuroprotective properties of the Wnt signaling activation against the toxicity of Aβ peptide. In cultured hippocampal neurons, exposure to Aβ aggregates causes a decrease in endogenous β-catenin levels, and this effect was overcome by direct activation of the pathway with Wnt-3a conditioned media [117, 129]. The protective effect of Wnt-3a against the toxicity of Aβ oligomers was shown to be mediated by Fz1 receptor, since this effect is modulated by the expression levels of Fz1 in both, PC12 cells and hippocampal neurons [14]. Overexpression of Fz1 significantly increased cell survival induced by Wnt-3a and diminished caspase-3 activation, while knocking-down the expression of the receptor by antisense oligonucleotides decreased the stabilization of β-catenin induced by Wnt-3a and decreased the neuroprotive effect elicited by this Wnt ligand [14].
In agreement with the effect of Wnt-3a, inhibition of GSK-3β by lithium protects hippocampal neurons from Aβ-induced damage. More importantly, in vivo lithium treatment of double transgenic APPswe/PSEN1ΔE9 mice, which is a well characterized in vivo model of AD that shows most hallmarks of the disease [140], reduced spatial memory impairment, decreased Aβ oligomers and the activation of astrocytes and microglia [141]. In vivo, lithium treatment activated the Wnt signaling as shown by the increase in β-catenin and by the inhibition of GSK-3β [141]. These studies suggest that the loss of normal Wnt/β-catenin signaling activity may be involved in the Aβ-dependent neurodegeneration observed in AD and that the activation of the pathway might have beneficial effects for the treatment of the disease [12].
APPswe/PSEN1ΔE9 mice show decreased levels of adult neurogenesis [142]. In these mice, we evaluated the effect of hypoxia on the generation of new neurons in the hippocampus. As previously mentioned hypoxia induces the activation of the Wnt/β-catenin signaling pathway in the hippocampus of wild-type mice. Mice were exposed to low oxygen and neurogenesis was evaluated by incorporation of BrdU and double staining with DCX. It was determined that hypoxia is a strong stimulator of neurogenesis in AD mice (our unpublished results). Currently we are evaluating whether this effect is related to the activation of the canonical Wnt pathway. Also, we have observed that voluntary wheel running strongly increased neurogenesis in APPswe/PSEN1ΔE9 mice and also decreased Aβ burden and tau phosphorylation (our unpublished results). As previously mentioned, voluntary running was found to increase de novo expression of Wnt-3 [101], suggesting that the effects observed in runner AD mice could involve the activation of the Wnt signaling pathway.
In addition to the role of the canonical Wnt signaling, we have studied whether Wnt-5a is able to protect neurons against Aβ oligomers synaptotoxicity [143]. Synaptic failure is an early event in AD, and soluble Aβ oligomers are proposed to be responsible for the synaptic pathology that occurs before the plaque deposition and neuronal death [74, 144]. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic transmission in hippocampal slices demonstrated that Wnt-5a prevents the decrease in the amplitude of fEPSP and EPSCs induced by Aβ oligomers, indicating that Wnt-5a prevents the synaptic damage triggered by Aβ [143]. Moreover, Wnt-5a prevented the decrease in the postsynaptic density scaffold protein PSD-95 and synaptic loss in cultured hippocampal neurons [143], supporting that Wnt-5a improves synaptic function in the presence of Aβ.
Additionally, the activation of several signaling pathways that crosstalk with the Wnt pathway also supports the neuroprotective potential of the Wnt cascades in AD [12].
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6. Conclusions
As we have discussed throughout this Chapter, the Wnt signaling pathway has fundamental roles in the development and function of the CNS. As discussed, the canonical and non-canonical Wnt signaling cascades have shown to be important for the formation and structure of central synapses, and in addition to the structural effects, Wnt ligands acutely modulate synaptic transmission and plasticity. Also, in the adult brain the Wnt pathway is one of the signaling cascades that regulates the generation of new neurons in neurogenic niches. Importantly, different stimuli that regulate neurogenesis involve the regulation of the Wnt signaling, implicating this pathway as a relevant player in the modulation of this physiological process.
Considering all the discussed roles of Wnts, it was expected that alterations in the Wnt cascades leads to diseases associated to the nervous system. In fact, deregulation of the Wnt pathway has been related to mental disorders, mood disorders and neurodegenerative diseases. As we have discussed, a bulk of evidence associate Wnt dysfunction to AD, and strongly point to a neuroprotective potential of the Wnt cascades as a therapeutic approach. Future work should focus on explore the therapeutic benefits of stimulating the Wnt signaling pathway in vivo.
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Acknowledgments
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We thank to Felipe G. Serrano for his contribution in the artwork. This work was supported by Grants from FONDECYT (N°1120156) and the Basal Center of Excellence in Science and Technology (CONICYT-PFB12/2007) to NCI and FONDECYT (N°11110012) and Insertion of Postdoctoral Researchers in the Academy (CONICYT-79090027) to LV-N.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/43854.pdf",chapterXML:"https://mts.intechopen.com/source/xml/43854.xml",downloadPdfUrl:"/chapter/pdf-download/43854",previewPdfUrl:"/chapter/pdf-preview/43854",totalDownloads:2518,totalViews:472,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"April 30th 2012",dateReviewed:null,datePrePublished:null,datePublished:"March 27th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/43854",risUrl:"/chapter/ris/43854",book:{slug:"trends-in-cell-signaling-pathways-in-neuronal-fate-decision"},signatures:"Nibaldo C. Inestrosa and Lorena Varela-Nallar",authors:[{id:"157413",title:"Dr.",name:"Nibaldo C.",middleName:null,surname:"Inestrosa",fullName:"Nibaldo C. Inestrosa",slug:"nibaldo-c.-inestrosa",email:"ninestrosa@bio.puc.cl",position:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"157428",title:"Dr.",name:"Lorena",middleName:null,surname:"Varela-Nallar",fullName:"Lorena Varela-Nallar",slug:"lorena-varela-nallar",email:"lpvarela@uc.cl",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The Wnt signaling pathway: Canonical and non–canonical signaling cascades",level:"1"},{id:"sec_3",title:"3. Roles of the Wnt signaling pathway at central synapses",level:"1"},{id:"sec_4",title:"4. Role of Wnt signaling in adult neurogenesis",level:"1"},{id:"sec_5",title:"5. Wnt signaling in Alzheimer’s disease",level:"1"},{id:"sec_6",title:"6. 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M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuruvilla\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreenberg\n\t\t\t\t\t\t\tM. E\n\t\t\t\t\t\t\n\t\t\t\t\tWnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci U S A 2012\n\t\t\t\t\t109\n\t\t\t\t\t11\n\t\t\t\t\t4044\n\t\t\t\t\t51\n\t\t\t\t\n\t\t\t'},{id:"B9",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAngers\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoon\n\t\t\t\t\t\t\tR. T\n\t\t\t\t\t\t\n\t\t\t\t\tProximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 2009\n\t\t\t\t\t10\n\t\t\t\t\t7\n\t\t\t\t\t468\n\t\t\t\t\t77\n\t\t\t\t\n\t\t\t'},{id:"B10",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVeeman\n\t\t\t\t\t\t\tM. T\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAxelrod\n\t\t\t\t\t\t\tJ. D\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoon\n\t\t\t\t\t\t\tR. T\n\t\t\t\t\t\t\n\t\t\t\t\tA second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Developmental cell 2003\n\t\t\t\t\t5\n\t\t\t\t\t3\n\t\t\t\t\t367\n\t\t\t\t\t77\n\t\t\t\t\n\t\t\t'},{id:"B11",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalinas\n\t\t\t\t\t\t\tP. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZou\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\tWnt signaling in neural circuit assembly. Annu Rev Neurosci 2008\n\t\t\t\t\t31\n\t\t\t\t\t339\n\t\t\t\t\n\t\t\t'},{id:"B12",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArenas\n\t\t\t\t\t\t\tE\n\t\t\t\t\t\t\n\t\t\t\t\tEmerging roles of Wnts in the adult nervous system. Nature reviews 2010\n\t\t\t\t\t11\n\t\t\t\t\t2\n\t\t\t\t\t77\n\t\t\t\t\t86\n\t\t\t\t\n\t\t\t'},{id:"B13",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimogori\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVansant\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaik\n\t\t\t\t\t\t\tE\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrove\n\t\t\t\t\t\t\tE. A\n\t\t\t\t\t\t\n\t\t\t\t\tMembers of the Wnt, Fz, and Frp gene families expressed in postnatal mouse cerebral cortex. J Comp Neurol 2004\n\t\t\t\t\t473\n\t\t\t\t\t4\n\t\t\t\t\t496\n\t\t\t\t\t510\n\t\t\t\t\n\t\t\t'},{id:"B14",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChacon\n\t\t\t\t\t\t\tM. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Nallar\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\tFrizzled-1 is involved in the neuroprotective effect of Wnt3a against Abeta oligomers. J Cell Physiol 2008\n\t\t\t\t\t217\n\t\t\t\t\t1\n\t\t\t\t\t215\n\t\t\t\t\t27\n\t\t\t\t\n\t\t\t'},{id:"B15",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Nallar\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlfaro\n\t\t\t\t\t\t\tI. E\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSerrano\n\t\t\t\t\t\t\tF. G\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParodi\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\tWingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci U S A 2010\n\t\t\t\t\t107\n\t\t\t\t\t49\n\t\t\t\t\t21164\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCerpa\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGambrill\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarria\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tRegulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci 2011\n\t\t\t\t\t31\n\t\t\t\t\t26\n\t\t\t\t\t9466\n\t\t\t\t\t71\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tC. S\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tS. J\n\t\t\t\t\t\t\n\t\t\t\t\tActivity-dependent synaptic Wnt release regulates hippocampal long term potentiation. 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C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJessberger\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\tProspero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc Natl Acad Sci U S A (2011). , 108(14), 5807-12.\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLie\n\t\t\t\t\t\t\tD. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tColamarino\n\t\t\t\t\t\t\tS. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tH. J\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDesire\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMira\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConsiglio\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLein\n\t\t\t\t\t\t\tE. S\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJessberger\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLansford\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDearie\n\t\t\t\t\t\t\tA. R\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\tWnt signalling regulates adult hippocampal neurogenesis. Nature 2005\n\t\t\t\t\t437\n\t\t\t\t\t7063\n\t\t\t\t\t1370\n\t\t\t\t\t5\n\t\t\t\t\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tX\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\tThe Wnt /beta-catenin signaling pathway in the adult neurogenesis. 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Cell Signal 2007\n\t\t\t\t\t19\n\t\t\t\t\t4\n\t\t\t\t\t659\n\t\t\t\t\t71\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCadigan\n\t\t\t\t\t\t\tK. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tY. I\n\t\t\t\t\t\t\n\t\t\t\t\tWnt signaling: complexity at the surface. J Cell Sci 2006Pt 3) 395-402.\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAberle\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBauer\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStappert\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKispert\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKemler\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\tbeta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 1997\n\t\t\t\t\t16\n\t\t\t\t\t13\n\t\t\t\t\t3797\n\t\t\t\t\t804\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkeda\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKishida\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamamoto\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurai\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoyama\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKikuchi\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tAxin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J 1998\n\t\t\t\t\t17\n\t\t\t\t\t5\n\t\t\t\t\t1371\n\t\t\t\t\t84\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKishida\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamamoto\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkeda\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKishida\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakamoto\n\t\t\t\t\t\t\tI\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoyama\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKikuchi\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tAxin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem 1998\n\t\t\t\t\t273\n\t\t\t\t\t18\n\t\t\t\t\t10823\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHart\n\t\t\t\t\t\t\tM. J\n\t\t\t\t\t\t\n\t\t\t\t\tde los Santos R, Albert IN, Rubinfeld B,Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 1998\n\t\t\t\t\t8\n\t\t\t\t\t10\n\t\t\t\t\t573\n\t\t\t\t\t81\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItoh\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrupnik\n\t\t\t\t\t\t\tV. E\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSokol\n\t\t\t\t\t\t\tS. Y\n\t\t\t\t\t\t\n\t\t\t\t\tAxis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and beta-catenin. Curr Biol 1998\n\t\t\t\t\t8\n\t\t\t\t\t10\n\t\t\t\t\t591\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakanaka\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeiss\n\t\t\t\t\t\t\tJ. B\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilliams\n\t\t\t\t\t\t\tL. T\n\t\t\t\t\t\t\n\t\t\t\t\tBridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci U S A 1998\n\t\t\t\t\t95\n\t\t\t\t\t6\n\t\t\t\t\t3020\n\t\t\t\t\t3\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSemenov\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaeg\n\t\t\t\t\t\t\tG. H\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTan\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tZ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tX\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tX\n\t\t\t\t\t\t\n\t\t\t\t\tControl of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002\n\t\t\t\t\t108\n\t\t\t\t\t6\n\t\t\t\t\t837\n\t\t\t\t\t47\n\t\t\t\t\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tV. S\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\n\t\t\t\t\t\t\tS. S\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoersema\n\t\t\t\t\t\t\tP. J\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLow\n\t\t\t\t\t\t\tT. Y\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarthaus\n\t\t\t\t\t\t\tW. R\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGerlach\n\t\t\t\t\t\t\tJ. P\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMohammed\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeck\n\t\t\t\t\t\t\tA. J\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaurice\n\t\t\t\t\t\t\tM. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMahmoudi\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClevers\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\tWnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell 2012\n\t\t\t\t\t149\n\t\t\t\t\t6\n\t\t\t\t\t1245\n\t\t\t\t\t56\n\t\t\t\t\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBehrens\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVon Kries\n\t\t\t\t\t\t\tJ. P\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuhl\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruhn\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWedlich\n\t\t\t\t\t\t\tD\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrosschedl\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBirchmeier\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\tFunctional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996\n\t\t\t\t\t382\n\t\t\t\t\t6592\n\t\t\t\t\t638\n\t\t\t\t\t42\n\t\t\t\t\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEastman\n\t\t\t\t\t\t\tQ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrosschedl\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\tRegulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 1999\n\t\t\t\t\t11\n\t\t\t\t\t2\n\t\t\t\t\t233\n\t\t\t\t\t40\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuber\n\t\t\t\t\t\t\tO\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorn\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMclaughlin\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhsugi\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHerrmann\n\t\t\t\t\t\t\tB. G\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKemler\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\tNuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev 1996\n\t\t\t\t\t59\n\t\t\t\t\t1\n\t\t\t\t\t3\n\t\t\t\t\t10\n\t\t\t\t\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoose\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMolenaar\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeterson\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHurenkamp\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrantjes\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoerer\n\t\t\t\t\t\t\tP\n\t\t\t\t\t\t\n\t\t\t\t\tvan de Wetering M, Destree O,Clevers H. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 1998\n\t\t\t\t\t395\n\t\t\t\t\t6702\n\t\t\t\t\t608\n\t\t\t\t\t12\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCavallo\n\t\t\t\t\t\t\tR. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tR. T\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoline\n\t\t\t\t\t\t\tM. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoose\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPolevoy\n\t\t\t\t\t\t\tG. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClevers\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeifer\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBejsovec\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tDrosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 1998\n\t\t\t\t\t395\n\t\t\t\t\t6702\n\t\t\t\t\t604\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHurlstone\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tClevers H. T-cell factors: turn-ons and turn-offs. EMBO J 2002\n\t\t\t\t\t21\n\t\t\t\t\t10\n\t\t\t\t\t2303\n\t\t\t\t\t11\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFernandez\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMische\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCourey\n\t\t\t\t\t\t\tA. J\n\t\t\t\t\t\t\n\t\t\t\t\tA functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev 1999\n\t\t\t\t\t13\n\t\t\t\t\t17\n\t\t\t\t\t2218\n\t\t\t\t\t30\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArrazola\n\t\t\t\t\t\t\tM. S\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Nallar\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tColombres\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToledo\n\t\t\t\t\t\t\tE. 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Neuron 2006\n\t\t\t\t\t50\n\t\t\t\t\t6\n\t\t\t\t\t897\n\t\t\t\t\t909\n\t\t\t\t\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGogolla\n\t\t\t\t\t\t\tN\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGalimberti\n\t\t\t\t\t\t\tI\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeguchi\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaroni\n\t\t\t\t\t\t\tP\n\t\t\t\t\t\t\n\t\t\t\t\tWnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus. Neuron 2009\n\t\t\t\t\t62\n\t\t\t\t\t4\n\t\t\t\t\t510\n\t\t\t\t\t25\n\t\t\t\t\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Nallar\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamirez\n\t\t\t\t\t\t\tV. T\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGonzalez-billault\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\tFrizzled receptors in neurons: From growth cones to the synapse. Cytoskeleton (Hoboken) 2012\n\t\t\t\t\t69\n\t\t\t\t\t7\n\t\t\t\t\t528\n\t\t\t\t\t34\n\t\t\t\t\n\t\t\t'},{id:"B86",body:'\n\t\t\t\tZhai, R, Olias, G, Chung, W. J, Lester R. A, tom Dieck, S, Langnaese, K, Kreutz, M. R, Kindler, S, Gundelfinger, E. D, & Garner C. C. Temporal appearance of the presynaptic cytomatrix protein bassoon during synaptogenesis. Mol Cell Neurosci 2000\n\t\t\t\t\t15\n\t\t\t\t\t5\n\t\t\t\t\t417\n\t\t\t\t\t28\n\t\t\t\t\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSahores\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGibb\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalinas\n\t\t\t\t\t\t\tP. C\n\t\t\t\t\t\t\n\t\t\t\t\tFrizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development (Cambridge, England) 2010\n\t\t\t\t\t137\n\t\t\t\t\t13\n\t\t\t\t\t2215\n\t\t\t\t\t25\n\t\t\t\t\n\t\t\t'},{id:"B88",body:'\n\t\t\t\tAlvarez-Buylla, A, & Garcia-Verdugo, J. M. Neurogenesis in adult subventricular zone. J Neurosci 2002\n\t\t\t\t\t22\n\t\t\t\t\t3\n\t\t\t\t\t629\n\t\t\t\t\t34\n\t\t\t\t\n\t\t\t'},{id:"B89",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\tMammalian neural stem cells. Science (New York, N.Y.) (2000). 287\n\t\t\t\t\t5457\n\t\t\t\t\t1433\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B90",body:'\n\t\t\t\tZhao, C, Teng, E. M, Summers, R. G Jr, Ming, G. L, & Gage, F. H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 2006\n\t\t\t\t\t26\n\t\t\t\t\t1\n\t\t\t\t\t3\n\t\t\t\t\t11\n\t\t\t\t\n\t\t\t'},{id:"B91",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuh\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeng\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\tSignaling in adult neurogenesis. Annu Rev Cell Dev Biol (2009). , 25, 253-75.\n\t\t\t'},{id:"B92",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMing\n\t\t\t\t\t\t\tG. L\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\tAdult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 2011\n\t\t\t\t\t70\n\t\t\t\t\t4\n\t\t\t\t\t687\n\t\t\t\t\t702\n\t\t\t\t\n\t\t\t'},{id:"B93",body:'\n\t\t\t\tJessberger, S, Clark, R. E, Broadbent, N. J, Clemenson, G. D Jr, Consiglio, A, Lie, D. C, Squire, L. R, & Gage, F. H. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem 2009\n\t\t\t\t\t16\n\t\t\t\t\t2\n\t\t\t\t\t147\n\t\t\t\t\t54\n\t\t\t\t\n\t\t\t'},{id:"B94",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdachi\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMirzadeh\n\t\t\t\t\t\t\tZ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakaguchi\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamashita\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNikolcheva\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGotoh\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeltz\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGong\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawase\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlvarez-Buylla\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkano\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSawamoto\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\tBeta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone. Stem Cells 2007\n\t\t\t\t\t25\n\t\t\t\t\t11\n\t\t\t\t\t2827\n\t\t\t\t\t36\n\t\t\t\t\n\t\t\t'},{id:"B95",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQu\n\t\t\t\t\t\t\tQ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYe\n\t\t\t\t\t\t\tP\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tR. T\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEvans\n\t\t\t\t\t\t\tR. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShi\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\tOrphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol 2010sup 1\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B96",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tZ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUre\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbles\n\t\t\t\t\t\t\tJ. L\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLagace\n\t\t\t\t\t\t\tD. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNave\n\t\t\t\t\t\t\tK. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoebbels\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEisch\n\t\t\t\t\t\t\tA. J\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHsieh\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\tNeurod1 is essential for the survival and maturation of adult-born neurons. Nat Neurosci 2009\n\t\t\t\t\t12\n\t\t\t\t\t9\n\t\t\t\t\t1090\n\t\t\t\t\t2\n\t\t\t\t\n\t\t\t'},{id:"B97",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeisseroth\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSingla\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToda\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMonje\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPalmer\n\t\t\t\t\t\t\tT. D\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMalenka\n\t\t\t\t\t\t\tR. C\n\t\t\t\t\t\t\n\t\t\t\t\tExcitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 2004\n\t\t\t\t\t42\n\t\t\t\t\t4\n\t\t\t\t\t535\n\t\t\t\t\t52\n\t\t\t\t\n\t\t\t'},{id:"B98",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGe\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoh\n\t\t\t\t\t\t\tE. L\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSailor\n\t\t\t\t\t\t\tK. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitabatake\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMing\n\t\t\t\t\t\t\tG. L\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\tGABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 2006\n\t\t\t\t\t439\n\t\t\t\t\t7076\n\t\t\t\t\t589\n\t\t\t\t\t93\n\t\t\t\t\n\t\t\t'},{id:"B99",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJagasia\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteib\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEnglberger\n\t\t\t\t\t\t\tE\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHerold\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFaus-kessler\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaxe\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLie\n\t\t\t\t\t\t\tD. C\n\t\t\t\t\t\t\n\t\t\t\t\tGABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 2009\n\t\t\t\t\t29\n\t\t\t\t\t25\n\t\t\t\t\t7966\n\t\t\t\t\t77\n\t\t\t\t\n\t\t\t'},{id:"B100",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTozuka\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukuda\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNamba\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeki\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHisatsune\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\tGABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 2005\n\t\t\t\t\t47\n\t\t\t\t\t6\n\t\t\t\t\t803\n\t\t\t\t\t15\n\t\t\t\t\n\t\t\t'},{id:"B101",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkamoto\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInoue\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwamura\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerashima\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoya\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAsashima\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuwabara\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\tReduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. Faseb J 2011\n\t\t\t\t\t25\n\t\t\t\t\t10\n\t\t\t\t\t3570\n\t\t\t\t\t82\n\t\t\t\t\n\t\t\t'},{id:"B102",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuhn\n\t\t\t\t\t\t\tH. G\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDickinson-anson\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\tNeurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996\n\t\t\t\t\t16\n\t\t\t\t\t6\n\t\t\t\t\t2027\n\t\t\t\t\t33\n\t\t\t\t\n\t\t\t'},{id:"B103",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Nallar\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAranguiz\n\t\t\t\t\t\t\tF. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbbott\n\t\t\t\t\t\t\tA. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSlater\n\t\t\t\t\t\t\tP. G\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\tAdult hippocampal neurogenesis in aging and Alzheimer’s disease. Birth Defects Res C Embryo Today 2010\n\t\t\t\t\t90\n\t\t\t\t\t4\n\t\t\t\t\t284\n\t\t\t\t\t96\n\t\t\t\t\n\t\t\t'},{id:"B104",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan Praag\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKempermann\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. H\n\t\t\t\t\t\t\n\t\t\t\t\tRunning increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999\n\t\t\t\t\t2\n\t\t\t\t\t3\n\t\t\t\t\t266\n\t\t\t\t\t70\n\t\t\t\t\n\t\t\t'},{id:"B105",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWexler\n\t\t\t\t\t\t\tE. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaucer\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKornblum\n\t\t\t\t\t\t\tH. I\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPalmer\n\t\t\t\t\t\t\tT. D\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeschwind\n\t\t\t\t\t\t\tD. H\n\t\t\t\t\t\t\n\t\t\t\t\tEndogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells 2009\n\t\t\t\t\t27\n\t\t\t\t\t5\n\t\t\t\t\t1130\n\t\t\t\t\t41\n\t\t\t\t\n\t\t\t'},{id:"B106",body:'\n\t\t\t\tShi, Y. Chichung Lie, D, Taupin, P, Nakashima, K, Ray, J, Yu, R. T, Gage, F. H, & Evans, R. M. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 2004\n\t\t\t\t\t427\n\t\t\t\t\t6969\n\t\t\t\t\t78\n\t\t\t\t\t83\n\t\t\t\t\n\t\t\t'},{id:"B107",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQu\n\t\t\t\t\t\t\tQ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakashima\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShi\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\tNuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain. Mol Endocrinol 2008\n\t\t\t\t\t22\n\t\t\t\t\t1\n\t\t\t\t\t56\n\t\t\t\t\t64\n\t\t\t\t\n\t\t\t'},{id:"B108",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tH. K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBelz\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBock\n\t\t\t\t\t\t\tD\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakacs\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLichter\n\t\t\t\t\t\t\tP\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChai\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchutz\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\tThe nuclear receptor tailless is required for neurogenesis in the adult subventricular zone. Genes Dev 2008\n\t\t\t\t\t22\n\t\t\t\t\t18\n\t\t\t\t\t2473\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B109",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tC. L\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZou\n\t\t\t\t\t\t\tY\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tW\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGage\n\t\t\t\t\t\t\tF. 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Nat Rev Genet 2004\n\t\t\t\t\t5\n\t\t\t\t\t9\n\t\t\t\t\t691\n\t\t\t\t\t701\n\t\t\t\t\n\t\t\t'},{id:"B126",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosi\n\t\t\t\t\t\t\tM. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuccarini\n\t\t\t\t\t\t\tI\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrossi\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiorentini\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpillantini\n\t\t\t\t\t\t\tM. G\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrisco\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScali\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGianfriddo\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaricasole\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerstappen\n\t\t\t\t\t\t\tG. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCasamenti\n\t\t\t\t\t\t\tF\n\t\t\t\t\t\t\n\t\t\t\t\tIncreased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem 2010\n\t\t\t\t\t112\n\t\t\t\t\t6\n\t\t\t\t\t1539\n\t\t\t\t\t51\n\t\t\t\t\n\t\t\t'},{id:"B127",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaruso\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMotolese\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIacovelli\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaraci\n\t\t\t\t\t\t\tF\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCopani\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNicoletti\n\t\t\t\t\t\t\tF\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerstappen\n\t\t\t\t\t\t\tG. C\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaviraghi\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaricasole\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\tInhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells. J Neurochem 2006\n\t\t\t\t\t98\n\t\t\t\t\t2\n\t\t\t\t\t364\n\t\t\t\t\t71\n\t\t\t\t\n\t\t\t'},{id:"B128",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMagdesian\n\t\t\t\t\t\t\tM. H\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarvalho\n\t\t\t\t\t\t\tM. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMendes\n\t\t\t\t\t\t\tF. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaraiva\n\t\t\t\t\t\t\tL. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJuliano\n\t\t\t\t\t\t\tM. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJuliano\n\t\t\t\t\t\t\tL\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarcia-abreu\n\t\t\t\t\t\t\tJ\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerreira\n\t\t\t\t\t\t\tS. T\n\t\t\t\t\t\t\n\t\t\t\t\tAmyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. J Biol Chem 2008\n\t\t\t\t\t283\n\t\t\t\t\t14\n\t\t\t\t\t9359\n\t\t\t\t\t68\n\t\t\t\t\n\t\t\t'},{id:"B129",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlvarez\n\t\t\t\t\t\t\tA. R\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGodoy\n\t\t\t\t\t\t\tJ. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMullendorff\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOlivares\n\t\t\t\t\t\t\tG. H\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBronfman\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInestrosa\n\t\t\t\t\t\t\tN. C\n\t\t\t\t\t\t\n\t\t\t\t\tWnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res 2004\n\t\t\t\t\t297\n\t\t\t\t\t1\n\t\t\t\t\t186\n\t\t\t\t\t96\n\t\t\t\t\n\t\t\t'},{id:"B130",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPurro\n\t\t\t\t\t\t\tS. A\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDickins\n\t\t\t\t\t\t\tE. M\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalinas\n\t\t\t\t\t\t\tP. C\n\t\t\t\t\t\t\n\t\t\t\t\tThe secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. J Neurosci 2010\n\t\t\t\t\t32\n\t\t\t\t\t10\n\t\t\t\t\t3492\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B131",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBallard\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGauthier\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCorbett\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrayne\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAarsland\n\t\t\t\t\t\t\tD\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\n\t\t\t\t\t\t\tE\n\t\t\t\t\t\t\n\t\t\t\t\tAlzheimer’s disease. Lancet 2011\n\t\t\t\t\t377\n\t\t\t\t\t9770\n\t\t\t\t\t1019\n\t\t\t\t\t31\n\t\t\t\t\n\t\t\t'},{id:"B132",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChurcher\n\t\t\t\t\t\t\tI\n\t\t\t\t\t\t\n\t\t\t\t\tTau therapeutic strategies for the treatment of Alzheimer’s disease. Curr Top Med Chem 2006\n\t\t\t\t\t6\n\t\t\t\t\t6\n\t\t\t\t\t579\n\t\t\t\t\t95\n\t\t\t\t\n\t\t\t'},{id:"B133",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHooper\n\t\t\t\t\t\t\tC\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKillick\n\t\t\t\t\t\t\tR\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLovestone\n\t\t\t\t\t\t\tS\n\t\t\t\t\t\t\n\t\t\t\t\tThe GSK3 hypothesis of Alzheimer’s disease. J Neurochem 2008\n\t\t\t\t\t104\n\t\t\t\t\t6\n\t\t\t\t\t1433\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B134",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakashima\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichel\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMercken\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoshi\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshiguro\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImahori\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\tExposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 1996\n\t\t\t\t\t203\n\t\t\t\t\t1\n\t\t\t\t\t33\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B135",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakashima\n\t\t\t\t\t\t\tA\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHonda\n\t\t\t\t\t\t\tT\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYasutake\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichel\n\t\t\t\t\t\t\tG\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurayama\n\t\t\t\t\t\t\tO\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurayama\n\t\t\t\t\t\t\tM\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshiguro\n\t\t\t\t\t\t\tK\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamaguchi\n\t\t\t\t\t\t\tH\n\t\t\t\t\t\t\n\t\t\t\t\tActivation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. 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Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile
Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile
'}],corrections:null},book:{id:"3148",title:"Trends in Cell Signaling Pathways in Neuronal Fate Decision",subtitle:null,fullTitle:"Trends in Cell Signaling Pathways in Neuronal Fate Decision",slug:"trends-in-cell-signaling-pathways-in-neuronal-fate-decision",publishedDate:"March 27th 2013",bookSignature:"Sabine Wislet-Gendebien",coverURL:"https://cdn.intechopen.com/books/images_new/3148.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"65329",title:"Dr.",name:"Sabine",middleName:null,surname:"Wislet",slug:"sabine-wislet",fullName:"Sabine Wislet"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"42065",title:"Role of TGF-β Signaling in Neurogenic Regions After Brain Injury",slug:"role-of-tgf-signaling-in-neurogenic-regions-after-brain-injury",totalDownloads:4431,totalCrossrefCites:3,signatures:"Sonia Villapol, Trevor T. Logan and Aviva J. 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1. Introduction
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Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. It is caused by a genetic mutation affecting cellular growth regulation, therefore resulting in disrupted pathways and formation of multiple tumors in the body. Ocular involvement is an important part of the disease as it may be required for the diagnosis. Although some manifestations are only of diagnostic value such as Lisch nodules, other ocular involvement can be vision threatening like glaucoma and optic nerve gliomas. Therefore, this chapter aims to explore how this disease can affect various structures of the eye and some histopathological changes that may be seen in some.
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2. Types of neurofibromatosis
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Neurofibromatosis is caused by a gene mutation affecting a tumor suppressor protein resulting in uncontrolled proliferation of neural cells that can involve various parts of the body such as nerves, skin, and eyes. It is classified into two types based on the location of the mutated gene. Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease, is caused by a mutation in the gene NF-1 located on chromosome 17. This leads to a dysfunctional tumor suppressor protein known as neurofibromin. As a result, NF-1 manifests as multiple benign tumors in the body such as plexiform neurofibromas, Lisch nodules, and optic nerve gliomas. NF-1 is inherited as autosomal dominant trait but may be sporadic in about 50% of the cases [1]. Ophthalmic manifestations are of diagnostic value in NF. Table 1 shows the criteria that are used for the diagnosis of NF-1 [2]. Three out of the total seven may involve ocular structures. Therefore, an individual may be diagnosed with NF-1 solely on his ophthalmic exam.
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Six or more café au lait macules (greatest diameter of >5 mm in prepubertal individuals and > 15 mm in postpubertal individuals)
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Two or more neurofibromas of any type or one plexiform neurofibroma
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Axillary or inguinal freckling.
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Optic glioma
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Two or more Lisch nodules (iris hamartomas)
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A distinctive osseous lesion (sphenoid dysplasia or tibial pseudarthrosis)
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A first degree relative with NF1
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Table 1.
Diagnostic criteria for NF1 (two or more must be present).
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Neurofibromatosis type 2 (NF-2) is caused by a chromosome 22 mutation in the gene encoding for the protein merlin or schwannomin, which is also a tumor suppressor protein. Dysregulation of this gene results in overproduction of Schwann cells. Therefore, the most prominent feature of this disease is bilateral vestibular schwannomas occurring in almost 90% of the patients. It may also affect different structures in the body causing tumors such as optic meningiomas and gliomas. Similar to NF-1, it is inherited in autosomal dominant fashion but may be sporadic [2].
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Clinical presentation of both diseases may overlap as they both affect cellular growth of neural tissue. This chapter will be discussing ocular manifestations that are seen in NF highlighting the importance of ophthalmic examination in these patients.
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3. Intraocular manifestations
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3.1 Iris
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Various intraocular conditions have been described in NF, most commonly, iris hamartomas. Iris hamartomas is a hallmark feature in NF-1 and is therefore considered one of the diagnostic criteria. Histologically, Lisch nodules have been described to be a collection of spindle cells that are melanocytic in origin [3]. They usually occur during childhood and increase in size and number with aging. They are typically seen under slit-lamp examination; are described as round elevated nodules within the iris, measuring around 2–3 mm in size; and are brown to yellow in color (Figure 1). Lisch nodules are typically bilateral; however, unilateral nodules have been reported previously in some types of NF [4].
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Figure 1.
Slit-lamp photo of an iris showing Lisch nodules in a patient diagnosed with neurofibromatosis.
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3.2 Glaucoma
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Glaucoma has been found to occur in about 1 in 300 NF-1 patients [5]. Patients with orbito-facial involvement have been linked to higher rates of glaucoma at 23–50% [6, 7, 8]. It was also found that patients with eyelid plexiform neurofibromas have ipsilateral globe enlargement up to 36 mm axial length [6]. Although glaucoma in NF is not common, it has been studied due to the visual burden it may cause. Various mechanisms have been described in the pathogenesis of glaucoma in these patients. The most commonly described mechanism is the presence of neurofibromas in the angle causing aqueous outflow obstruction [6]. Other suggested processes include secondary angle closure due to the anterior displacement of the peripheral iris by an abnormally thickened ciliary body or developmental anomalies in the angle [7].
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Moreover, congenital ectropion uvea has been linked to refractory glaucoma in patients with NF. Histologically, endothelialization of the anterior chamber angle has been observed in these eyes. It has been hypothesized that loss of the NF gene and therefore RAS–RAF–ERK–MAPK pathway activation may be the cause of endothelial overgrowth in these patients [9]. It is difficult to link one mechanism causing glaucoma in NF as most cases are probably multifactorial as described above.
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3.3 Lens
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Lens opacities are of importance in NF-2 as they may be the first sign to suggest the diagnosis during childhood [10]. NF-2 typically causes posterior subcapsular cataract or cortical cataract and occurs in 60–80% of patients with the disease [10, 11].
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3.4 Retina and choroid
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Retinal astrocytic hamartomas are benign tumors that usually affect the optic nerve. They clinically resemble a small white mulberry and are mostly linked to tuberous sclerosis but have been reported in NF patients as well. Rarely, those lesions may extend to the peripheral retina and cause devastating complications such as neovascular glaucoma and retinal detachment. Other retinal lesions described in NF patients include combined hamartoma of the retina and retinal pigment epithelium (CHR-RPE) and retinal capillary hemangiomatosis [12, 13, 14].
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In the past, choroidal involvement was thought to be uncommon in NF patients as it was difficult to visualize subtle changes with fundus examination and conventional angiography. However, with the development of new diagnostic technologies such as optical coherence tomography (OCT), choroidal changes have been found to reach up to 100% of NF patients [15]. Uveal neurofibromatosis has been also demonstrated histopathologically within the choroid (Figure 2) [9].
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Figure 2.
The choroid in a neurofibroma patient with spindle and ganglion cells (original magnification X400 hematoxylin and eosin).
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4. Periocular and orbital manifestations
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4.1 Optic pathway glioma
\n
Optic pathway gliomas are low-grade tumors which are classified as WHO grade I pilocytic astrocytomas. They usually occur early in childhood in around 5–25% of NF patients [15]. Although benign, these tumors can cause significant visual loss due to the direct compression of the optic nerve. They may arise anywhere along the optic pathway from the optic nerve to the chiasm and radiation. When those tumors involve the orbit, they may cause unilateral proptosis, strabismus, and decreased vision. Due to the nature of these tumors and the catastrophic consequences they may have, annual screening for all NF patients less than 10 years of age and then every 2 years until the age of 18 years is recommended [16].
One of the most characteristic findings in NF-1 patients and a hallmark of the disease is plexiform neurofibroma. It is a congenital tumor usually unilateral involving the eyelid, orbit, and periorbital area. It starts early in childhood with rapid growth that slows down after puberty. OPPN affects approximately 10% of patients with NF-1, and it carries a risk for malignant transformation in about 10%. It is considered a benign tumor of peripheral nerves with spindle cell proliferation and wavy filamentous pattern of growth (Figures 3 and 4). Histologically, they may be composed of mixed diffuse and plexiform types (Figure 5) with proliferation of Schwann cells, fibroblasts, and mast cells. Plexiform neurofibromas are similar but are encapsulated with the proliferations being surrounded by perineurium (Figure 6). Plexiform neurofibromas are of clinical significance as they are often described clinically as a “bag of worms” and can grow to form bulging masses that can be quiet disfiguring to a patient leading to social embarrassment. They usually cause mechanical ptosis when involving the upper eyelid (Figure 7), which may lead to amblyopia in children. Further progression to orbital and periorbital areas lead to proptosis, strabismus, and displacement of the globe. Rarely, plexiform neurofibromas may also involve the conjunctiva of the eye. Sphenoid wing dysplasia can be found in patients with OPPN affecting the same side and usually present with proptosis and pulsatile exophthalmos. Plexiform neurofibroma is a highly recurrent tumor, especially in orbito-facial area and in younger patients [17, 18, 19].
\n
Figure 3.
Neurofibroma of the diffuse type with spindle cell proliferation (original magnification X400 hematoxylin and eosin).
\n
Figure 4.
The same diffuse type of neurofibroma with spindle cells expressing s-100 staining (original magnification X200 S-100).
\n
Figure 5.
Mixed plexiform (black star) and diffuse (red arrowhead) neurofibromatosis (original magnification X100 hematoxylin and eosin).
\n
Figure 6.
An area of typical plexiform neurofibroma (original magnification X100 hematoxylin and eosin).
\n
Figure 7.
A child with a plexiform neurofibroma of the right upper eyelid causing significant ptosis that affects the visual axis.
\n
\n
\n
\n
5. Imaging
\n
A high-resolution magnetic resonance imaging (MRI) with and without contrast of the brain and orbits should be performed in all NF-suspected patients to confirm the diagnosis and to monitor for the progression. CT scan should be avoided if possible, because of its radiation and the risk of malignant transformation of neurofibroma [19].
\n
\n
\n
6. Management
\n
Patients with NF need a multidisciplinary team of pediatric ophthalmology, neuro-ophthalmology, oculoplastic surgeon, neuro-oncology, and genetics. All children diagnosed with NF should have regular ophthalmological examinations every 6 months until the age of visual maturation (7 years) to detect and treat amblyopia, glaucoma, or strabismus. Also, serial MRI might be needed. The frequency of examination and imaging should be tailored according to the patient needs and disease progression. Early diagnosis and management of ophthalmic related issues are important and usually treated by supportive methods.
\n
In children, surgical interventions for neurofibroma and its related strabismus should be reserved for severe cosmesis and visually threatening conditions because of its highly recurrent nature. Adults with neurofibroma usually need an aggressive and definitive surgical approach to prevent recurrence with the possibility of several surgeries. The most common indications for surgical debulking are cosmetic, decreased vision, progressive involvement of a vital structure, and functional deficits. Any significant increase in the growth rate of neurofibroma that is unusual for the patient age should be worrisome for malignant transformation [19].
\n
\n
\n
7. Conclusion
\n
In conclusion, neurofibromatosis can affect the eye and ocular adnexa in various ways. It is of importance to recognize ocular involvement in such patients in order to help earlier diagnosis of treatable conditions that can be vision-threatening.
\n
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"neurofibromatosis, glaucoma, cataract, retinal hamartoma, Lisch nodules, choroid, optic nerve, glioma, plexiform neurofibroma, diffuse neurofibroma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69966.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69966.xml",downloadPdfUrl:"/chapter/pdf-download/69966",previewPdfUrl:"/chapter/pdf-preview/69966",totalDownloads:329,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 6th 2019",dateReviewed:"October 4th 2019",datePrePublished:"November 7th 2019",datePublished:"May 20th 2020",dateFinished:null,readingETA:"0",abstract:"Neurofibromatosis (NF) is an inherited disease affecting multiple systems in the body. The eye is frequently affected in neurofibromatosis, and therefore ocular manifestations play a major role in the diagnosis of NF. This chapter aims to explore the spectrum of ocular manifestations found in neurofibromatosis highlighting the importance of ophthalmic exam in these patients. It will describe various intraocular manifestations involving the iris, lens, and retina. It will be focusing on glaucoma and the pathogenesis behind it in this group of patients. Moreover, periorbital and orbital involvement such as skin neurofibromas and optic nerve gliomas will be discussed along with some of their histopathological findings.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69966",risUrl:"/chapter/ris/69966",signatures:"Hind M. Alkatan, Sawsan S. Bakry and Mohammad A. Alabduljabbar",book:{id:"8729",title:"Neurofibromatosis",subtitle:"Current Trends and Future Directions",fullTitle:"Neurofibromatosis - Current Trends and Future Directions",slug:"neurofibromatosis-current-trends-and-future-directions",publishedDate:"May 20th 2020",bookSignature:"Francesco Signorelli and Raffaella Messina",coverURL:"https://cdn.intechopen.com/books/images_new/8729.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"74494",title:"Dr.",name:"Francesco",middleName:null,surname:"Signorelli",slug:"francesco-signorelli",fullName:"Francesco Signorelli"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"223782",title:"Dr.",name:"Hind",middleName:"Manaa",surname:"Alkatan",fullName:"Hind Alkatan",slug:"hind-alkatan",email:"hindkatan@yahoo.com",position:null,institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"294678",title:"Dr.",name:"Sawsan S.",middleName:null,surname:"Bakry",fullName:"Sawsan S. Bakry",slug:"sawsan-s.-bakry",email:"sawsan.hajbakry@gmail.com",position:null,institution:null},{id:"310954",title:"Dr.",name:"Mohammad",middleName:"Abdullah",surname:"Alabduljabbar",fullName:"Mohammad Alabduljabbar",slug:"mohammad-alabduljabbar",email:"mabduljabbar@live.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Types of neurofibromatosis",level:"1"},{id:"sec_3",title:"3. Intraocular manifestations",level:"1"},{id:"sec_3_2",title:"3.1 Iris",level:"2"},{id:"sec_4_2",title:"3.2 Glaucoma",level:"2"},{id:"sec_5_2",title:"3.3 Lens",level:"2"},{id:"sec_6_2",title:"3.4 Retina and choroid",level:"2"},{id:"sec_8",title:"4. Periocular and orbital manifestations",level:"1"},{id:"sec_8_2",title:"4.1 Optic pathway glioma",level:"2"},{id:"sec_9_2",title:"4.2 Orbital-periorbital plexiform neurofibroma (OPPN)",level:"2"},{id:"sec_11",title:"5. Imaging",level:"1"},{id:"sec_12",title:"6. Management",level:"1"},{id:"sec_13",title:"7. Conclusion",level:"1"},{id:"sec_17",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nThomann K, Marks E, Adamczyk D. Primary Eyecare in Systemic Disease. 2nd ed. New York: McGraw-Hill; 2001\n'},{id:"B2",body:'\nEvans D. Medical management of neurofibromatosis. Paediatrics & Child Health. 2011;21(10):459-465\n'},{id:"B3",body:'\nWilliamson T, Garner A, Moore A. Structure of Lisch nodules in neurofibromatosis type 1. Ophthalmic Paediatrics and Genetics. 1991;12(1):11-17\n'},{id:"B4",body:'\nAdams E, Stewart K, Borges O, Darling T. Multiple, unilateral Lisch nodules in the absence of other manifestations of neurofibromatosis type 1. Case Reports in Ophthalmological Medicine. 2011;2011(854784):1-2\n'},{id:"B5",body:'\nGrant W, Walton D. Distinctive gonioscopic findings in glaucoma due to neurofibromatosis. Archives of Ophthalmology. 1968;79(2):127-134\n'},{id:"B6",body:'\nMorales J, Chaudhry I, Bosley T. Glaucoma and globe enlargement associated with Neurofibromatosis type 1. Ophthalmology. 2009;116(9):1725-1730\n'},{id:"B7",body:'\nThavikulwat A, Edward D, AlDarrab A, Vajaranant T. Pathophysiology and management of glaucoma associated with phakomatoses. Journal of Neuroscience Research. 2018;97(1):57-69\n'},{id:"B8",body:'\nKahook M, Schuman J, Epstein D. Chandler and Grant\'s Glaucoma. 5th ed. Baltimore: Williams & Wilkins; 2013\n'},{id:"B9",body:'\nEdward D, Morales J, Bouhenni R, Patil J, Edward P, Cummings T, et al. Congenital ectropion uvea and mechanisms of glaucoma in neurofibromatosis type 1. Ophthalmology. 2012;119(7):1485-1494\n'},{id:"B10",body:'\nKaiser-Kupfer M. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Archives of Ophthalmology. 1989;107(4):541\n'},{id:"B11",body:'\nEvans D, Lloyd S, Ramsden R. Neurofibromatosis type 2. Advances in Oto-Rhino-Laryngology. 2011;70:91-98\n'},{id:"B12",body:'\nGrant E, Trzupek K, Reiss J, Crow K, Messiaen L, Weleber R. Combined retinal hamartomas leading to the diagnosis of neurofibromatosis type 2. Ophthalmic Genetics. 2008;29(3):133-138\n'},{id:"B13",body:'\nMartin K, Rossi V, Ferrucci S, Pian D. Retinal astrocytic hamartoma. Optometry. 2010;81(5):221-233\n'},{id:"B14",body:'\nDestro M. Retinal manifestations of neurofibromatosis. Archives of Ophthalmology. 1991;109(5):662\n'},{id:"B15",body:'\nKinori M, Hodgson N, Zeid J. Ophthalmic manifestations in neurofibromatosis type 1. Survey of Ophthalmology. 2017;63(4):518-533\n'},{id:"B16",body:'\nListernick R, Ferner R, Liu G, Gutmann D. Optic pathway gliomas in neurofibromatosis-1: Controversies and recommendations. Annals of Neurology. 2007;61(3):189-198\n'},{id:"B17",body:'\nLewis R, Riccardi V. von Recklinghausen neurofibromatosis. Ophthalmology. 1981;88(4):348-354\n'},{id:"B18",body:'\nArun KP, Thomas Joseph P, Jaishankar HP, Abhinethra MS. Von Recklinghausens disease: A series of four cases with variable expression. Journal of Oral and Maxillofacial Surgery. 2015;14(Suppl 1):161-167. DOI: 10.1007/s12663-012-0399-x\n'},{id:"B19",body:'\nAvery RA, Katowitz JA, Fisher MJ, Heidary G, Dombi E, Packer RJ, et al. Orbital/periorbital plexiform neurofibromas in children with neurofibromatosis type 1: Multidisciplinary recommendations for care. Ophthalmology. 2017;124(1):123-132\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hind M. Alkatan",address:"hindkatan@yahoo.com",affiliation:'
Departments of Ophthalmology and Pathology, College of Medicine, King Saud University, Saudi Arabia
'},{corresp:null,contributorFullName:"Sawsan S. Bakry",address:null,affiliation:'
Neurology Department, College of Medicine, King Saud University, Saudi Arabia
'},{corresp:null,contributorFullName:"Mohammad A. Alabduljabbar",address:null,affiliation:'
King Khaled Eye Specialist Hospital, Saudi Arabia
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The Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
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The Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
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TERMINATION
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IntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
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In the event of termination, IntechOpen will notify the Author of the decision in writing.
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IntechOpen’s DUTIES AND RIGHTS
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Unless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
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IntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
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IntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
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IntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
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Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
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Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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Variation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
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Severance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
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No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
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Governing law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
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CORRESPONDING AUTHOR'S GRANT OF RIGHTS
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The foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
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The Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
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All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
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The Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
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AUTHOR'S DUTIES
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When distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
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The Author agrees to:
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Define the topic and title of the Work.
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Submit the complete manuscript; the Author assumes the responsibility for the published content, defining the sections of the Work and structuring the content and writing a foreword i.e. the introductory chapter of the Work.
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Submit all the corrections in due time.
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The Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
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All payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
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The Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
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The Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
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The Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
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AUTHOR'S WARRANTY
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The Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\n
The Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\n
The Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\n
The Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\n
Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
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TERMINATION
\n\n
IntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
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In the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\n
IntechOpen’s DUTIES AND RIGHTS
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Unless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\n
Unless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\n
IntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\n
IntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n
IntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\n
MISCELLANEOUS
\n\n
Further Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n
Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n
Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\n
Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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Variation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\n
Severance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n
No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\n
Governing law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
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Policy last updated: 2018-09-11
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