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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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Related in: MedlinePlus

The impact of the engrailed genes in the development of the central nervous system and the mesodiencephalic dopaminergic system. (A) Engrailed proteins are key players in diverse processes during embryonic development of the central nervous system (CNS), including patterning, axonal guidance and neuron specification. (B) Engrailed proteins are essential in mesodiencephalic dopaminergic (mdDA) neuron development from an early stage, where they are involved in morphogenesis and mdDA neurogenesis, and in the adult, where they play a role in mdDA neuron maintenance E, embryonic day.
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Figure 2: The impact of the engrailed genes in the development of the central nervous system and the mesodiencephalic dopaminergic system. (A) Engrailed proteins are key players in diverse processes during embryonic development of the central nervous system (CNS), including patterning, axonal guidance and neuron specification. (B) Engrailed proteins are essential in mesodiencephalic dopaminergic (mdDA) neuron development from an early stage, where they are involved in morphogenesis and mdDA neurogenesis, and in the adult, where they play a role in mdDA neuron maintenance E, embryonic day.

Mentions: Today, after two decades of research, a multitude of evidence has been produced establishing engrailed proteins as key players in the embryonic development of the CNS (Figure 2A). Up until now, it has been shown that they are involved in multiple developmental processes: the regionalization in early embryogenesis, including isthmic organization [13,67,70-72]; neuronal identity, such as the control of glial-neuronal fate in the grasshopper [73] and serotonergic midline neurons in Drosophila [74]; axonal outgrowth and pathfinding in insects, birds and mammals [75-80]; and the identity specification of subsets of vertebrate interneurons in the spinal cord [68,81]. Engrailed proteins, besides functioning as transcription factors (localized in the nucleus), have also been characterized as secreting survival factors [80,82-84], where about 5% of the engrailed protein is found associated with membrane vesicles, becoming secreted and internalized by cells [82,85,86]. Furthermore, En1 secretion appears to be a regulated process [87]. These studies have shown that engrailed proteins can function as signaling molecules, acting in a paracrine manner in mdDA neurons. In a recent study, mdDA neuronal loss in En1+/- adult mice was antagonized by En2 recombinant protein infusions in the midbrain [88], showing both the ability of engrailed to act as a signaling molecule and suggesting a biochemical equivalence between En1 and En2.


En1 and Wnt signaling in midbrain dopaminergic neuronal development.

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

The impact of the engrailed genes in the development of the central nervous system and the mesodiencephalic dopaminergic system. (A) Engrailed proteins are key players in diverse processes during embryonic development of the central nervous system (CNS), including patterning, axonal guidance and neuron specification. (B) Engrailed proteins are essential in mesodiencephalic dopaminergic (mdDA) neuron development from an early stage, where they are involved in morphogenesis and mdDA neurogenesis, and in the adult, where they play a role in mdDA neuron maintenance E, embryonic day.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The impact of the engrailed genes in the development of the central nervous system and the mesodiencephalic dopaminergic system. (A) Engrailed proteins are key players in diverse processes during embryonic development of the central nervous system (CNS), including patterning, axonal guidance and neuron specification. (B) Engrailed proteins are essential in mesodiencephalic dopaminergic (mdDA) neuron development from an early stage, where they are involved in morphogenesis and mdDA neurogenesis, and in the adult, where they play a role in mdDA neuron maintenance E, embryonic day.
Mentions: Today, after two decades of research, a multitude of evidence has been produced establishing engrailed proteins as key players in the embryonic development of the CNS (Figure 2A). Up until now, it has been shown that they are involved in multiple developmental processes: the regionalization in early embryogenesis, including isthmic organization [13,67,70-72]; neuronal identity, such as the control of glial-neuronal fate in the grasshopper [73] and serotonergic midline neurons in Drosophila [74]; axonal outgrowth and pathfinding in insects, birds and mammals [75-80]; and the identity specification of subsets of vertebrate interneurons in the spinal cord [68,81]. Engrailed proteins, besides functioning as transcription factors (localized in the nucleus), have also been characterized as secreting survival factors [80,82-84], where about 5% of the engrailed protein is found associated with membrane vesicles, becoming secreted and internalized by cells [82,85,86]. Furthermore, En1 secretion appears to be a regulated process [87]. These studies have shown that engrailed proteins can function as signaling molecules, acting in a paracrine manner in mdDA neurons. In a recent study, mdDA neuronal loss in En1+/- adult mice was antagonized by En2 recombinant protein infusions in the midbrain [88], showing both the ability of engrailed to act as a signaling molecule and suggesting a biochemical equivalence between En1 and En2.

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