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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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Spatial and temporal developmental stages leading to mesodiencephalic dopaminergic neurogenesis. (A) Sagittal and coronal schematic sections showing the region in the developing central nervous system where mesodiencephalic dopaminergic (mdDA) neurons are born. Anterior-posterior patterning leads to the genesis of morphogenetic domains: telencephalon (Tel), rostral diencephalon (RD), midbrain (M) and hindbrain (H), whereas dorsal-ventral patterning results in crosswise subdivisions in the brain: floor plate (FP), basal plate (BP), alar plate (AP) and roof plate. The mdDA area encompasses the midbrain and prosomeres (P) 1 to 3. The floor plate is divided in three main areas: the ventricular zone (VZ), the intermediate zone (IZ) and the marginal zone (MZ). (B) Molecular cascades leading to mdDA neurogenesis, illustrated by three different stages from top to bottom. The key genes driving mdDA development are represented. En1 and Wnt signaling are required already in early development, being essential throughout mdDA development, from early patterning up to the induction of mdDA neurons. Although we placed En1 in all these developmental stages, a molecular characterization of how En1 contributes to each of these has not yet been performed. It remains to be seen as well whether Wnt signaling is active in a settled mdDA neuron (after embryonic day (E)14). The progenitor pool is located in the VZ and its progeny migrates to the IZ, where it differentiates into post-mitotic mdDA precursors, expressing Nurr1 and L-aromatic amino acid decarboxylase (Aadc). Later on, after E12, mdDA neurons start to differentiate, expressing mdDA key identity genes like Pitx3, Th and Vmat2. The differentiated settled mdDA neurons localize in the MZ.
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Figure 1: Spatial and temporal developmental stages leading to mesodiencephalic dopaminergic neurogenesis. (A) Sagittal and coronal schematic sections showing the region in the developing central nervous system where mesodiencephalic dopaminergic (mdDA) neurons are born. Anterior-posterior patterning leads to the genesis of morphogenetic domains: telencephalon (Tel), rostral diencephalon (RD), midbrain (M) and hindbrain (H), whereas dorsal-ventral patterning results in crosswise subdivisions in the brain: floor plate (FP), basal plate (BP), alar plate (AP) and roof plate. The mdDA area encompasses the midbrain and prosomeres (P) 1 to 3. The floor plate is divided in three main areas: the ventricular zone (VZ), the intermediate zone (IZ) and the marginal zone (MZ). (B) Molecular cascades leading to mdDA neurogenesis, illustrated by three different stages from top to bottom. The key genes driving mdDA development are represented. En1 and Wnt signaling are required already in early development, being essential throughout mdDA development, from early patterning up to the induction of mdDA neurons. Although we placed En1 in all these developmental stages, a molecular characterization of how En1 contributes to each of these has not yet been performed. It remains to be seen as well whether Wnt signaling is active in a settled mdDA neuron (after embryonic day (E)14). The progenitor pool is located in the VZ and its progeny migrates to the IZ, where it differentiates into post-mitotic mdDA precursors, expressing Nurr1 and L-aromatic amino acid decarboxylase (Aadc). Later on, after E12, mdDA neurons start to differentiate, expressing mdDA key identity genes like Pitx3, Th and Vmat2. The differentiated settled mdDA neurons localize in the MZ.

Mentions: The development of an organ, such as the midbrain, implies the sequential occurrence of developmental cascades over time, while these might overlap in time and space [12-14]. During early neuronal induction and patterning, a precise molecular coding along the anterior-posterior and dorsal-ventral axis in the developing neural tube provides positional cues that are crucial in pattern formation [15-17]. Anterior-posterior patterning leads to the genesis of morphogenetic domains - forebrain, midbrain, isthmus and hindbrain - whereas dorsal-ventral patterning results in crosswise subdivisions in the brain throughout the neuroaxis - floor plate, basal plate, alar plate and roof plate [16,18,19] (Figure 1A).


En1 and Wnt signaling in midbrain dopaminergic neuronal development.

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

Spatial and temporal developmental stages leading to mesodiencephalic dopaminergic neurogenesis. (A) Sagittal and coronal schematic sections showing the region in the developing central nervous system where mesodiencephalic dopaminergic (mdDA) neurons are born. Anterior-posterior patterning leads to the genesis of morphogenetic domains: telencephalon (Tel), rostral diencephalon (RD), midbrain (M) and hindbrain (H), whereas dorsal-ventral patterning results in crosswise subdivisions in the brain: floor plate (FP), basal plate (BP), alar plate (AP) and roof plate. The mdDA area encompasses the midbrain and prosomeres (P) 1 to 3. The floor plate is divided in three main areas: the ventricular zone (VZ), the intermediate zone (IZ) and the marginal zone (MZ). (B) Molecular cascades leading to mdDA neurogenesis, illustrated by three different stages from top to bottom. The key genes driving mdDA development are represented. En1 and Wnt signaling are required already in early development, being essential throughout mdDA development, from early patterning up to the induction of mdDA neurons. Although we placed En1 in all these developmental stages, a molecular characterization of how En1 contributes to each of these has not yet been performed. It remains to be seen as well whether Wnt signaling is active in a settled mdDA neuron (after embryonic day (E)14). The progenitor pool is located in the VZ and its progeny migrates to the IZ, where it differentiates into post-mitotic mdDA precursors, expressing Nurr1 and L-aromatic amino acid decarboxylase (Aadc). Later on, after E12, mdDA neurons start to differentiate, expressing mdDA key identity genes like Pitx3, Th and Vmat2. The differentiated settled mdDA neurons localize in the MZ.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Spatial and temporal developmental stages leading to mesodiencephalic dopaminergic neurogenesis. (A) Sagittal and coronal schematic sections showing the region in the developing central nervous system where mesodiencephalic dopaminergic (mdDA) neurons are born. Anterior-posterior patterning leads to the genesis of morphogenetic domains: telencephalon (Tel), rostral diencephalon (RD), midbrain (M) and hindbrain (H), whereas dorsal-ventral patterning results in crosswise subdivisions in the brain: floor plate (FP), basal plate (BP), alar plate (AP) and roof plate. The mdDA area encompasses the midbrain and prosomeres (P) 1 to 3. The floor plate is divided in three main areas: the ventricular zone (VZ), the intermediate zone (IZ) and the marginal zone (MZ). (B) Molecular cascades leading to mdDA neurogenesis, illustrated by three different stages from top to bottom. The key genes driving mdDA development are represented. En1 and Wnt signaling are required already in early development, being essential throughout mdDA development, from early patterning up to the induction of mdDA neurons. Although we placed En1 in all these developmental stages, a molecular characterization of how En1 contributes to each of these has not yet been performed. It remains to be seen as well whether Wnt signaling is active in a settled mdDA neuron (after embryonic day (E)14). The progenitor pool is located in the VZ and its progeny migrates to the IZ, where it differentiates into post-mitotic mdDA precursors, expressing Nurr1 and L-aromatic amino acid decarboxylase (Aadc). Later on, after E12, mdDA neurons start to differentiate, expressing mdDA key identity genes like Pitx3, Th and Vmat2. The differentiated settled mdDA neurons localize in the MZ.
Mentions: The development of an organ, such as the midbrain, implies the sequential occurrence of developmental cascades over time, while these might overlap in time and space [12-14]. During early neuronal induction and patterning, a precise molecular coding along the anterior-posterior and dorsal-ventral axis in the developing neural tube provides positional cues that are crucial in pattern formation [15-17]. Anterior-posterior patterning leads to the genesis of morphogenetic domains - forebrain, midbrain, isthmus and hindbrain - whereas dorsal-ventral patterning results in crosswise subdivisions in the brain throughout the neuroaxis - floor plate, basal plate, alar plate and roof plate [16,18,19] (Figure 1A).

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