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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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Canonical Wnt signaling mechanism. (1) Wnts bind to Frizzled (Fz) transmembrane receptors and low-density lipoprotein receptor-related protein (Lrp) co-receptors (2) triggering the dissolution of the 'β-catenin destruction complex', resulting in (3) β-catenin not being marked for degradation (asterisk) thereby accumulating in the cytoplasm and (4) translocating to the nucleus. (5) Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (Tcf/Lef) family of DNA-binding factors to form a transcriptional complex that binds target promoter sequences via a specific DNA-binding domain in TCFs, mediating Wnt target gene expression. APC, adenomatous polyposis coli.
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Figure 3: Canonical Wnt signaling mechanism. (1) Wnts bind to Frizzled (Fz) transmembrane receptors and low-density lipoprotein receptor-related protein (Lrp) co-receptors (2) triggering the dissolution of the 'β-catenin destruction complex', resulting in (3) β-catenin not being marked for degradation (asterisk) thereby accumulating in the cytoplasm and (4) translocating to the nucleus. (5) Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (Tcf/Lef) family of DNA-binding factors to form a transcriptional complex that binds target promoter sequences via a specific DNA-binding domain in TCFs, mediating Wnt target gene expression. APC, adenomatous polyposis coli.

Mentions: In the absence of Wnt stimulation, β-catenin is tagged for degradation by a cytoplasmic 'β-catenin destruction complex'. This complex is assembled by the scaffolding protein Axin and comprises glycogen synthase kinase (GSK)3β, casein kinase 1 and the adenomatous polyposis coli (APC) protein and others, which function by capturing 'surplus' β-catenin that is not involved in cell adhesion [122,132]. Once β-catenin is bound by Axin and APC, which act by efficiently positioning β-catenin and the kinases together, phosphorylation of β-catenin occurs by a dual kinase mechanism, whereby phosphorylation by casein kinase I triggers further phosphorylation by GSK3β [141]. This tagging results in β-catenin being recognized by β-Trcp, a ubiquitin ligase, causing β-catenin ubiquitination and subsequent proteasomal degradation [142]. In this manner, despite being continuously synthesized in the cell, the levels of cytosolic β-catenin are kept low, thus preventing it from accumulating in the nucleus. When Wnts bind to Fz transmembrane receptors and low-density lipoprotein receptor-related protein co-receptors (Lrp5 or Lrp6; Figure 3(1)), the scaffolding protein dishevelled (Dvl) joins this receptor complex, causing sequestration of Axin and, thereby, the dissolution of the β-catenin destruction complex [143-147] (Figure 3(2)). Consequently, β-catenin is not marked for degradation and is stabilized as a hypophosphorylated form, accumulating in the cytoplasm (Figure 3(3)), with preferential nuclear localization (Figure 3(4)). Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (TCF/LEF) family of DNA-binding factors, which bind to target promoter sequences via a specific DNA-binding domain in TCFs to form a transcriptional complex that mediates Wnt target gene expression [122,123] (Figure 3(5)). Furthermore, β-catenin is essential as a docking platform for various transcriptional co-activators and chromatin remodeling complexes to stimulate transcription [107,148].


En1 and Wnt signaling in midbrain dopaminergic neuronal development.

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

Canonical Wnt signaling mechanism. (1) Wnts bind to Frizzled (Fz) transmembrane receptors and low-density lipoprotein receptor-related protein (Lrp) co-receptors (2) triggering the dissolution of the 'β-catenin destruction complex', resulting in (3) β-catenin not being marked for degradation (asterisk) thereby accumulating in the cytoplasm and (4) translocating to the nucleus. (5) Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (Tcf/Lef) family of DNA-binding factors to form a transcriptional complex that binds target promoter sequences via a specific DNA-binding domain in TCFs, mediating Wnt target gene expression. APC, adenomatous polyposis coli.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Canonical Wnt signaling mechanism. (1) Wnts bind to Frizzled (Fz) transmembrane receptors and low-density lipoprotein receptor-related protein (Lrp) co-receptors (2) triggering the dissolution of the 'β-catenin destruction complex', resulting in (3) β-catenin not being marked for degradation (asterisk) thereby accumulating in the cytoplasm and (4) translocating to the nucleus. (5) Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (Tcf/Lef) family of DNA-binding factors to form a transcriptional complex that binds target promoter sequences via a specific DNA-binding domain in TCFs, mediating Wnt target gene expression. APC, adenomatous polyposis coli.
Mentions: In the absence of Wnt stimulation, β-catenin is tagged for degradation by a cytoplasmic 'β-catenin destruction complex'. This complex is assembled by the scaffolding protein Axin and comprises glycogen synthase kinase (GSK)3β, casein kinase 1 and the adenomatous polyposis coli (APC) protein and others, which function by capturing 'surplus' β-catenin that is not involved in cell adhesion [122,132]. Once β-catenin is bound by Axin and APC, which act by efficiently positioning β-catenin and the kinases together, phosphorylation of β-catenin occurs by a dual kinase mechanism, whereby phosphorylation by casein kinase I triggers further phosphorylation by GSK3β [141]. This tagging results in β-catenin being recognized by β-Trcp, a ubiquitin ligase, causing β-catenin ubiquitination and subsequent proteasomal degradation [142]. In this manner, despite being continuously synthesized in the cell, the levels of cytosolic β-catenin are kept low, thus preventing it from accumulating in the nucleus. When Wnts bind to Fz transmembrane receptors and low-density lipoprotein receptor-related protein co-receptors (Lrp5 or Lrp6; Figure 3(1)), the scaffolding protein dishevelled (Dvl) joins this receptor complex, causing sequestration of Axin and, thereby, the dissolution of the β-catenin destruction complex [143-147] (Figure 3(2)). Consequently, β-catenin is not marked for degradation and is stabilized as a hypophosphorylated form, accumulating in the cytoplasm (Figure 3(3)), with preferential nuclear localization (Figure 3(4)). Once in the nucleus, β-catenin binds to the T cell factor/lymphoid enhancer factor (TCF/LEF) family of DNA-binding factors, which bind to target promoter sequences via a specific DNA-binding domain in TCFs to form a transcriptional complex that mediates Wnt target gene expression [122,123] (Figure 3(5)). Furthermore, β-catenin is essential as a docking platform for various transcriptional co-activators and chromatin remodeling complexes to stimulate transcription [107,148].

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