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En1 and Wnt signaling in midbrain dopaminergic neuronal development.

Alves dos Santos MT, Smidt MP - Neural Dev (2011)

Bottom Line: Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development.The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron.In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor En1 and the canonical Wnt pathway, highlighting recent findings on their relevance--and interplay--in the development and maintenance of the mdDA system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Rudolf Magnus Institute of Neuroscience, Department of Neurosciences and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

ABSTRACT
Dopaminergic neurons of the ventral mesodiencephalon are affected in significant health disorders such as Parkinson's disease, schizophrenia, and addiction. The ultimate goal of current research endeavors is to improve the clinical treatment of such disorders, such as providing a protocol for cell replacement therapy in Parkinson's disease that will successfully promote the specific differentiation of a stem cell into a dopaminergic neuronal phenotype. Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development. The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron. In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor En1 and the canonical Wnt pathway, highlighting recent findings on their relevance--and interplay--in the development and maintenance of the mdDA system.

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Interplay between Wnt, Nurr1 and En1 signaling in vitro and in vivo. (A) Model adapted from Kitagawa et al. [156]: Wnt signaling via β-catenin enhances the transcriptional activity of Nurr1 in cells at Nurr1 responsive elements (NREs). In the absence of β-catenin, Nurr1 associates with T cell factor/lymphoid enhancer factor (TCF/LEF) in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with TCF/LEF for Nurr1 binding, resulting in the disruption of the co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators. (B) Model adapted from Kitagawa et al. [156]: on the other hand, Nurr1 was observed to slightly modulate, in a negative way, the canonical Wnt signaling through association with the TCF/LEF region. After Wnt stimulation, β-catenin competed with Nurr1 for Lef binding on the TCF/LEF promoter site and disrupted Nurr1 binding, promoting Wnt-target gene transcription. (C) Several studies in Drosophila and chick embryos have described interactions between En1/engrailed (en) and the Wnt/wg signaling pathway whereby engrailed expression is dependent on Wnt/wg signaling and vice versa. However, in Drosophila, engrailed expressing cells did not have active wg signaling. From mice studies it is known that Wnt signaling regulates En1 expression early in midbrain development. Whether the reverse happens in the mouse midbrain is not known. (D) In one cell culture study [216], it was observed that En1 can function as a negative regulator of β-catenin transcriptional activity in a post-translational manner (that is, by affecting β-catenin protein levels only). (E) Three questions remain currently unsolved: first, whether En1 cooperates with Nurr1 during mdDA development; second, whether Nurr1, En1 and canonical Wnt signaling cooperate in later stages of mdDA neuron development, such as in mdDA neuron specification; and third, whether Nurr1 and/or En1 regulate canonical Wnt signaling during mdDA neuron development.
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Figure 5: Interplay between Wnt, Nurr1 and En1 signaling in vitro and in vivo. (A) Model adapted from Kitagawa et al. [156]: Wnt signaling via β-catenin enhances the transcriptional activity of Nurr1 in cells at Nurr1 responsive elements (NREs). In the absence of β-catenin, Nurr1 associates with T cell factor/lymphoid enhancer factor (TCF/LEF) in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with TCF/LEF for Nurr1 binding, resulting in the disruption of the co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators. (B) Model adapted from Kitagawa et al. [156]: on the other hand, Nurr1 was observed to slightly modulate, in a negative way, the canonical Wnt signaling through association with the TCF/LEF region. After Wnt stimulation, β-catenin competed with Nurr1 for Lef binding on the TCF/LEF promoter site and disrupted Nurr1 binding, promoting Wnt-target gene transcription. (C) Several studies in Drosophila and chick embryos have described interactions between En1/engrailed (en) and the Wnt/wg signaling pathway whereby engrailed expression is dependent on Wnt/wg signaling and vice versa. However, in Drosophila, engrailed expressing cells did not have active wg signaling. From mice studies it is known that Wnt signaling regulates En1 expression early in midbrain development. Whether the reverse happens in the mouse midbrain is not known. (D) In one cell culture study [216], it was observed that En1 can function as a negative regulator of β-catenin transcriptional activity in a post-translational manner (that is, by affecting β-catenin protein levels only). (E) Three questions remain currently unsolved: first, whether En1 cooperates with Nurr1 during mdDA development; second, whether Nurr1, En1 and canonical Wnt signaling cooperate in later stages of mdDA neuron development, such as in mdDA neuron specification; and third, whether Nurr1 and/or En1 regulate canonical Wnt signaling during mdDA neuron development.

Mentions: It has been shown so far that activation of the Wnt/β-catenin pathway contributes to increased mdDA neurogenesis during development, that is, that it regulates the proliferation and differentiation of ventral mesodiencephalic Nurr1 precursors in vivo [203]. Taking into account the data as described, Kitagawa et al. [156] tested the possibility of Wnt signaling regulating Nurr1 activity, and found a convergence between Nurr1 transcriptional regulation and Wnt signaling in cell culture. In short, Wnt signaling via β-catenin enhanced the transcriptional activity of Nurr1 in cells, at Nurr1 responsive elements (NREs), leading to TH promoter activation (Figure 5A). In the absence of β-catenin, Nurr1 is associated with Lef1 in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with Lef1 for Nurr1 binding, resulting in the disruption of co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators, such as CBP (Creb binding protein) [156] (Figure 5A). β-catenin functions, so it seems, as a transcriptional cofactor for Nurr1. Small interfering RNAs targeting Nurr1 abolished CBP and β-catenin association with the NRE in the TH promoter [156]. On the other hand, Nurr1 was found to slightly modulate, in a negative way, the canonical Wnt signaling by being able to associate with the TCF/LEF region (Figure 5B). After Wnt stimulation, β-catenin would compete with Nurr1 for Lef1 binding on a TCF/LEF promoter site, such as the cyclin D1 promoter, and disrupt Nurr1 binding, promoting Wnt-target gene transcription [156]. A model to describe this mechanism was proposed and is shown in Figure 5A,B. Whether this model is valid for mdDA neuron differentiation and maintenance in vivo remains to be investigated. The question arises: do Nurr1 and β-catenin interact in vivo synergistically to drive Th expression? Previous studies strongly suggest that this is the case [204-206]. Importantly, besides the study from Kitagawa et al., synergistic interactions between β-catenin and several nuclear receptors have already been described [155]. Quite likely, β-catenin is involved in mdDA neurogeneis, cooperating with the Nurr1 transcription complex.


En1 and Wnt signaling in midbrain dopaminergic neuronal development.

Alves dos Santos MT, Smidt MP - Neural Dev (2011)

Interplay between Wnt, Nurr1 and En1 signaling in vitro and in vivo. (A) Model adapted from Kitagawa et al. [156]: Wnt signaling via β-catenin enhances the transcriptional activity of Nurr1 in cells at Nurr1 responsive elements (NREs). In the absence of β-catenin, Nurr1 associates with T cell factor/lymphoid enhancer factor (TCF/LEF) in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with TCF/LEF for Nurr1 binding, resulting in the disruption of the co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators. (B) Model adapted from Kitagawa et al. [156]: on the other hand, Nurr1 was observed to slightly modulate, in a negative way, the canonical Wnt signaling through association with the TCF/LEF region. After Wnt stimulation, β-catenin competed with Nurr1 for Lef binding on the TCF/LEF promoter site and disrupted Nurr1 binding, promoting Wnt-target gene transcription. (C) Several studies in Drosophila and chick embryos have described interactions between En1/engrailed (en) and the Wnt/wg signaling pathway whereby engrailed expression is dependent on Wnt/wg signaling and vice versa. However, in Drosophila, engrailed expressing cells did not have active wg signaling. From mice studies it is known that Wnt signaling regulates En1 expression early in midbrain development. Whether the reverse happens in the mouse midbrain is not known. (D) In one cell culture study [216], it was observed that En1 can function as a negative regulator of β-catenin transcriptional activity in a post-translational manner (that is, by affecting β-catenin protein levels only). (E) Three questions remain currently unsolved: first, whether En1 cooperates with Nurr1 during mdDA development; second, whether Nurr1, En1 and canonical Wnt signaling cooperate in later stages of mdDA neuron development, such as in mdDA neuron specification; and third, whether Nurr1 and/or En1 regulate canonical Wnt signaling during mdDA neuron development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104484&req=5

Figure 5: Interplay between Wnt, Nurr1 and En1 signaling in vitro and in vivo. (A) Model adapted from Kitagawa et al. [156]: Wnt signaling via β-catenin enhances the transcriptional activity of Nurr1 in cells at Nurr1 responsive elements (NREs). In the absence of β-catenin, Nurr1 associates with T cell factor/lymphoid enhancer factor (TCF/LEF) in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with TCF/LEF for Nurr1 binding, resulting in the disruption of the co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators. (B) Model adapted from Kitagawa et al. [156]: on the other hand, Nurr1 was observed to slightly modulate, in a negative way, the canonical Wnt signaling through association with the TCF/LEF region. After Wnt stimulation, β-catenin competed with Nurr1 for Lef binding on the TCF/LEF promoter site and disrupted Nurr1 binding, promoting Wnt-target gene transcription. (C) Several studies in Drosophila and chick embryos have described interactions between En1/engrailed (en) and the Wnt/wg signaling pathway whereby engrailed expression is dependent on Wnt/wg signaling and vice versa. However, in Drosophila, engrailed expressing cells did not have active wg signaling. From mice studies it is known that Wnt signaling regulates En1 expression early in midbrain development. Whether the reverse happens in the mouse midbrain is not known. (D) In one cell culture study [216], it was observed that En1 can function as a negative regulator of β-catenin transcriptional activity in a post-translational manner (that is, by affecting β-catenin protein levels only). (E) Three questions remain currently unsolved: first, whether En1 cooperates with Nurr1 during mdDA development; second, whether Nurr1, En1 and canonical Wnt signaling cooperate in later stages of mdDA neuron development, such as in mdDA neuron specification; and third, whether Nurr1 and/or En1 regulate canonical Wnt signaling during mdDA neuron development.
Mentions: It has been shown so far that activation of the Wnt/β-catenin pathway contributes to increased mdDA neurogenesis during development, that is, that it regulates the proliferation and differentiation of ventral mesodiencephalic Nurr1 precursors in vivo [203]. Taking into account the data as described, Kitagawa et al. [156] tested the possibility of Wnt signaling regulating Nurr1 activity, and found a convergence between Nurr1 transcriptional regulation and Wnt signaling in cell culture. In short, Wnt signaling via β-catenin enhanced the transcriptional activity of Nurr1 in cells, at Nurr1 responsive elements (NREs), leading to TH promoter activation (Figure 5A). In the absence of β-catenin, Nurr1 is associated with Lef1 in co-repressor complexes on NREs. After activation of Wnt signaling, β-catenin interacts with Nurr1 on NREs, competing with Lef1 for Nurr1 binding, resulting in the disruption of co-repressors from the Nurr1 complex and the concomitant recruitment of coactivators, such as CBP (Creb binding protein) [156] (Figure 5A). β-catenin functions, so it seems, as a transcriptional cofactor for Nurr1. Small interfering RNAs targeting Nurr1 abolished CBP and β-catenin association with the NRE in the TH promoter [156]. On the other hand, Nurr1 was found to slightly modulate, in a negative way, the canonical Wnt signaling by being able to associate with the TCF/LEF region (Figure 5B). After Wnt stimulation, β-catenin would compete with Nurr1 for Lef1 binding on a TCF/LEF promoter site, such as the cyclin D1 promoter, and disrupt Nurr1 binding, promoting Wnt-target gene transcription [156]. A model to describe this mechanism was proposed and is shown in Figure 5A,B. Whether this model is valid for mdDA neuron differentiation and maintenance in vivo remains to be investigated. The question arises: do Nurr1 and β-catenin interact in vivo synergistically to drive Th expression? Previous studies strongly suggest that this is the case [204-206]. Importantly, besides the study from Kitagawa et al., synergistic interactions between β-catenin and several nuclear receptors have already been described [155]. Quite likely, β-catenin is involved in mdDA neurogeneis, cooperating with the Nurr1 transcription complex.

Bottom Line: Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development.The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron.In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor En1 and the canonical Wnt pathway, highlighting recent findings on their relevance--and interplay--in the development and maintenance of the mdDA system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Rudolf Magnus Institute of Neuroscience, Department of Neurosciences and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

ABSTRACT
Dopaminergic neurons of the ventral mesodiencephalon are affected in significant health disorders such as Parkinson's disease, schizophrenia, and addiction. The ultimate goal of current research endeavors is to improve the clinical treatment of such disorders, such as providing a protocol for cell replacement therapy in Parkinson's disease that will successfully promote the specific differentiation of a stem cell into a dopaminergic neuronal phenotype. Decades of research on the developmental mechanisms of the mesodiencephalic dopaminergic (mdDA) system have led to the identification of many signaling pathways and transcription factors critical in its development. The unraveling of these pathways will help fill in the pieces of the puzzle that today dominates neurodevelopment research: how to make and maintain a mdDA neuron. In the present review, we provide an overview of the mdDA system, the processes and signaling molecules involved in its genesis, with a focus on the transcription factor En1 and the canonical Wnt pathway, highlighting recent findings on their relevance--and interplay--in the development and maintenance of the mdDA system.

Show MeSH
Related in: MedlinePlus