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Wnt Signaling in Neurogenesis during Aging and Physical Activity.

Chen M, Do H - Brain Sci (2012)

Bottom Line: Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway.Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals.Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, California State University, 5151 State University Drive, Los Angeles, CA 90032, USA. mchen@calstatela.edu.

ABSTRACT
Over the past decade, much progress has been made regarding our understanding of neurogenesis in both young and old animals and where it occurs throughout the lifespan, although the growth of new neurons declines with increasing age. In addition, physical activity can reverse this age-dependent decline in neurogenesis. Highly correlated with this decline is the degree of inter and intracellular Wnt signaling, the molecular mechanisms of which have only recently started to be elucidated. So far, most of what we know about intracellular signaling during/following exercise centers around the CREB/CRE initiated transcriptional events. Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway. Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals. Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.

No MeSH data available.


Related in: MedlinePlus

Exercise activates a wide variety of intracellular signal transduction pathways to promote neurogenesis of granule cells from neuroprogenitors in the dentate gyrus. Specifically applicable to neurogenesis, Wnt is released from neighboring astrocytes in a paracrine fashion, whereupon exercise increases Wnt signaling. Wnt binds its fzl receptor, complexed with LRP, and leading to the activation of Dshi, which, in turn, inactivates GSK3. The resulting accumulation of β-catenin (β-cat) in the cytoplasm and nucleus then binds to, and displaces, the gene regulatory proteins, LEF/TCF and Sox2 and the co-repressor, Groucho. β-Catenin then acts as a co-activator, and with transcription factors Prox1 and NeuroD1, stimulates the transcription of Wnt target genes. In addition, exercise also lifts the repressive MeCp2, thereby enhancing transcription. Normally, in the absence of exercise, Wnt3/3a is sent to the noncoding region of the granule cell, where L1 mobile elements are repressed during adult neurogenesis. Because L1 sequences contain the Wnt-regulatory element, the nearby genes can be indirectly up-regulated when the β-catenin/TCF-LEF complex is activated via Wnt signaling. In addition, exercise increases Wnt activity, leading to increased presynaptic protein and vesicle clustering, in turn leading to increased release of various neurotransmitters (norepinephrine, serotonin). Through a dizzying array of receptor and pathway cross-talk, these neurotransmitters, via GPCR signaling, can not only directly activate downstream PKA and subsequent transcription factor, CREB, thereby leading to the transcription of BDNF and related neurotrophic genes, but also activate other trophic factors (IGF-1, VEGF), thereby, in turn, activating a variety in intracellular signaling survival pathways (PI-3K, MAPK, CamKII), while simultaneously inhibiting apoptosis and inducing eNOS. Thus, both the Wnt regulatory element and the cAMP-response element (CRE) may participate (synergistically) to promote synaptogenesis, angiogenesis, proliferation, and neurogenesis.
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brainsci-02-00745-f004: Exercise activates a wide variety of intracellular signal transduction pathways to promote neurogenesis of granule cells from neuroprogenitors in the dentate gyrus. Specifically applicable to neurogenesis, Wnt is released from neighboring astrocytes in a paracrine fashion, whereupon exercise increases Wnt signaling. Wnt binds its fzl receptor, complexed with LRP, and leading to the activation of Dshi, which, in turn, inactivates GSK3. The resulting accumulation of β-catenin (β-cat) in the cytoplasm and nucleus then binds to, and displaces, the gene regulatory proteins, LEF/TCF and Sox2 and the co-repressor, Groucho. β-Catenin then acts as a co-activator, and with transcription factors Prox1 and NeuroD1, stimulates the transcription of Wnt target genes. In addition, exercise also lifts the repressive MeCp2, thereby enhancing transcription. Normally, in the absence of exercise, Wnt3/3a is sent to the noncoding region of the granule cell, where L1 mobile elements are repressed during adult neurogenesis. Because L1 sequences contain the Wnt-regulatory element, the nearby genes can be indirectly up-regulated when the β-catenin/TCF-LEF complex is activated via Wnt signaling. In addition, exercise increases Wnt activity, leading to increased presynaptic protein and vesicle clustering, in turn leading to increased release of various neurotransmitters (norepinephrine, serotonin). Through a dizzying array of receptor and pathway cross-talk, these neurotransmitters, via GPCR signaling, can not only directly activate downstream PKA and subsequent transcription factor, CREB, thereby leading to the transcription of BDNF and related neurotrophic genes, but also activate other trophic factors (IGF-1, VEGF), thereby, in turn, activating a variety in intracellular signaling survival pathways (PI-3K, MAPK, CamKII), while simultaneously inhibiting apoptosis and inducing eNOS. Thus, both the Wnt regulatory element and the cAMP-response element (CRE) may participate (synergistically) to promote synaptogenesis, angiogenesis, proliferation, and neurogenesis.

Mentions: Aging specifically compromises, whereas exercise increases, Wnt3 pathway signaling [126] and expression, thereby reversing the decline in neurogenesis brought on by age [124], as well as genes downstream of it [3,4] (Figure 4). In addition, as mentioned above, the study by Gogolla et al. [56] in which an enriched environment and Wnt7/7a application had the same effects on neurogenesis, it is possible that the running component of their living conditions was the crucial factor in eliciting neurogenesis [87]. The elegant studies by Okamoto et al. [124] have done much to contribute to our understanding of intercellular crosstalk between astrocytes and neural progenitor cells. In vivo, as age increases, astocytic Wnt3/3a expression and release decreases [126]. In addition, their in vitro experiments shed much light about the genetic regulation of Wnt-mediated neurogenesis. Their knockdowns of fzl1 and β-catenin using siRNAs lead to a down-regulation of the TCF/LEF reporter expression in both young and aged neural stem cells, indicating that the expression of Wnt canonical signaling pathway intermediates was not impaired in aged neural stem cells. Moreover, lentivirus expressing Wnt3 shRNA in young and aged astrocytic cultures resulted in increased tubulin III and synapsin I expression, indicating that astrocytic Wnt3a causes a neurogenic effect on adult hippocampal neural stem cells in an age-dependent manner and that such cells are primed for increased growth and neurotransmitter release. Such specific function of what will eventually be the granule cell may be regulated by the Prox1 promotor, which remains highly active throughout the maturation of the granule cell and may be responsible for specifying the neuronal phenotype [35]. Furthermore, Okamoto et al. [124] found that the dcx genes are among the L1 loci; specifically, the dcx promotor contains two L1 sequences regions with Wnt signaling regulatory sites. At the NeuroD1 promotor, binding of acetylated histone A3, β-catenin, and CREB gradually decreases with age, indicating that the aging process controls the repressed chromatin state. Physical activity and Wnt, through increased release of norepinephrine, may lift this repression (see Section 4 above; Figure 4).


Wnt Signaling in Neurogenesis during Aging and Physical Activity.

Chen M, Do H - Brain Sci (2012)

Exercise activates a wide variety of intracellular signal transduction pathways to promote neurogenesis of granule cells from neuroprogenitors in the dentate gyrus. Specifically applicable to neurogenesis, Wnt is released from neighboring astrocytes in a paracrine fashion, whereupon exercise increases Wnt signaling. Wnt binds its fzl receptor, complexed with LRP, and leading to the activation of Dshi, which, in turn, inactivates GSK3. The resulting accumulation of β-catenin (β-cat) in the cytoplasm and nucleus then binds to, and displaces, the gene regulatory proteins, LEF/TCF and Sox2 and the co-repressor, Groucho. β-Catenin then acts as a co-activator, and with transcription factors Prox1 and NeuroD1, stimulates the transcription of Wnt target genes. In addition, exercise also lifts the repressive MeCp2, thereby enhancing transcription. Normally, in the absence of exercise, Wnt3/3a is sent to the noncoding region of the granule cell, where L1 mobile elements are repressed during adult neurogenesis. Because L1 sequences contain the Wnt-regulatory element, the nearby genes can be indirectly up-regulated when the β-catenin/TCF-LEF complex is activated via Wnt signaling. In addition, exercise increases Wnt activity, leading to increased presynaptic protein and vesicle clustering, in turn leading to increased release of various neurotransmitters (norepinephrine, serotonin). Through a dizzying array of receptor and pathway cross-talk, these neurotransmitters, via GPCR signaling, can not only directly activate downstream PKA and subsequent transcription factor, CREB, thereby leading to the transcription of BDNF and related neurotrophic genes, but also activate other trophic factors (IGF-1, VEGF), thereby, in turn, activating a variety in intracellular signaling survival pathways (PI-3K, MAPK, CamKII), while simultaneously inhibiting apoptosis and inducing eNOS. Thus, both the Wnt regulatory element and the cAMP-response element (CRE) may participate (synergistically) to promote synaptogenesis, angiogenesis, proliferation, and neurogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061808&req=5

brainsci-02-00745-f004: Exercise activates a wide variety of intracellular signal transduction pathways to promote neurogenesis of granule cells from neuroprogenitors in the dentate gyrus. Specifically applicable to neurogenesis, Wnt is released from neighboring astrocytes in a paracrine fashion, whereupon exercise increases Wnt signaling. Wnt binds its fzl receptor, complexed with LRP, and leading to the activation of Dshi, which, in turn, inactivates GSK3. The resulting accumulation of β-catenin (β-cat) in the cytoplasm and nucleus then binds to, and displaces, the gene regulatory proteins, LEF/TCF and Sox2 and the co-repressor, Groucho. β-Catenin then acts as a co-activator, and with transcription factors Prox1 and NeuroD1, stimulates the transcription of Wnt target genes. In addition, exercise also lifts the repressive MeCp2, thereby enhancing transcription. Normally, in the absence of exercise, Wnt3/3a is sent to the noncoding region of the granule cell, where L1 mobile elements are repressed during adult neurogenesis. Because L1 sequences contain the Wnt-regulatory element, the nearby genes can be indirectly up-regulated when the β-catenin/TCF-LEF complex is activated via Wnt signaling. In addition, exercise increases Wnt activity, leading to increased presynaptic protein and vesicle clustering, in turn leading to increased release of various neurotransmitters (norepinephrine, serotonin). Through a dizzying array of receptor and pathway cross-talk, these neurotransmitters, via GPCR signaling, can not only directly activate downstream PKA and subsequent transcription factor, CREB, thereby leading to the transcription of BDNF and related neurotrophic genes, but also activate other trophic factors (IGF-1, VEGF), thereby, in turn, activating a variety in intracellular signaling survival pathways (PI-3K, MAPK, CamKII), while simultaneously inhibiting apoptosis and inducing eNOS. Thus, both the Wnt regulatory element and the cAMP-response element (CRE) may participate (synergistically) to promote synaptogenesis, angiogenesis, proliferation, and neurogenesis.
Mentions: Aging specifically compromises, whereas exercise increases, Wnt3 pathway signaling [126] and expression, thereby reversing the decline in neurogenesis brought on by age [124], as well as genes downstream of it [3,4] (Figure 4). In addition, as mentioned above, the study by Gogolla et al. [56] in which an enriched environment and Wnt7/7a application had the same effects on neurogenesis, it is possible that the running component of their living conditions was the crucial factor in eliciting neurogenesis [87]. The elegant studies by Okamoto et al. [124] have done much to contribute to our understanding of intercellular crosstalk between astrocytes and neural progenitor cells. In vivo, as age increases, astocytic Wnt3/3a expression and release decreases [126]. In addition, their in vitro experiments shed much light about the genetic regulation of Wnt-mediated neurogenesis. Their knockdowns of fzl1 and β-catenin using siRNAs lead to a down-regulation of the TCF/LEF reporter expression in both young and aged neural stem cells, indicating that the expression of Wnt canonical signaling pathway intermediates was not impaired in aged neural stem cells. Moreover, lentivirus expressing Wnt3 shRNA in young and aged astrocytic cultures resulted in increased tubulin III and synapsin I expression, indicating that astrocytic Wnt3a causes a neurogenic effect on adult hippocampal neural stem cells in an age-dependent manner and that such cells are primed for increased growth and neurotransmitter release. Such specific function of what will eventually be the granule cell may be regulated by the Prox1 promotor, which remains highly active throughout the maturation of the granule cell and may be responsible for specifying the neuronal phenotype [35]. Furthermore, Okamoto et al. [124] found that the dcx genes are among the L1 loci; specifically, the dcx promotor contains two L1 sequences regions with Wnt signaling regulatory sites. At the NeuroD1 promotor, binding of acetylated histone A3, β-catenin, and CREB gradually decreases with age, indicating that the aging process controls the repressed chromatin state. Physical activity and Wnt, through increased release of norepinephrine, may lift this repression (see Section 4 above; Figure 4).

Bottom Line: Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway.Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals.Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, California State University, 5151 State University Drive, Los Angeles, CA 90032, USA. mchen@calstatela.edu.

ABSTRACT
Over the past decade, much progress has been made regarding our understanding of neurogenesis in both young and old animals and where it occurs throughout the lifespan, although the growth of new neurons declines with increasing age. In addition, physical activity can reverse this age-dependent decline in neurogenesis. Highly correlated with this decline is the degree of inter and intracellular Wnt signaling, the molecular mechanisms of which have only recently started to be elucidated. So far, most of what we know about intracellular signaling during/following exercise centers around the CREB/CRE initiated transcriptional events. Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway. Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals. Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.

No MeSH data available.


Related in: MedlinePlus