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  • Review Article
  • Published:

How to make a mesodiencephalic dopaminergic neuron

Nature Reviews Neuroscience volume 8, pages 21–32 (2007)Cite this article

An Erratum to this article was published on 01 February 2007

Key Points

  • Mesodiencepahlic dopaminergic (mdDA) neurons consist of multiple molecular and functional distinguishable subsets, besides the 'old' anatomical definition of the substantia nigra pars compacta and the ventral tegmental area.

  • Subset specification is established through specific molecular coding of the ventricular zone in dorsoventral and rostrocaudal axes.

  • A combination of several signalling molecules including retinoic acid, WNTs, sonic hedgehog and transforming growth factors, as well as neurotrophic factors including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, influence the emergence and survival of mdDA neurons in addition to cell intrinsic molecular coding.

  • Specific mdDA subsets define specific connectivity to the forebrain regions such as the striatum and prefrontal cortex, providing specific functional networks.

  • Guidance molecules from the netrin–DCC (deleted in colorectal cancer), ROBO–SLIT and semaphorin–plexin–neuropilin pathways are essential for providing initial guidance rules to direct outgrowing mdDA axons towards the ventral forebrain.

  • Molecular programmes for mdDA development form the basis for embryonic stem (ES) cell engineering of mdDA neurons, including subset specification.

  • Transplantation paradigms with engineered ES cells, stem cells that are induced to develop the mdDA phenotype or embryonic mdDA cells should include axon guidance rules to ensure proper interactions and connectivity with striatal targets.

Abstract

Dopaminergic neurons located in the ventral mesodiencephalon are essential for the control of voluntary movement and the regulation of emotion, and are severely affected in neurodegenerative diseases such as Parkinson's disease. Recent advances in molecular biology and mouse genetics have helped to unravel the mechanisms involved in the development of mesodiencephalic dopaminergic (mdDA) neurons, including their specification, migration and differentiation, as well as the processes that govern axonal pathfinding and their specific patterns of connectivity and maintenance. Here, we follow the developmental path of these neurons with the goal of generating a molecular code that could be exploited in cell-replacement strategies to treat diseases such as Parkinson's disease.

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Figure 1: Anatomical classification of dopaminergic cell groups in the CNS.
Figure 2: The region in the CNS from which mdDA neurons emerge.
Figure 3: Guidance of mdDA axonal outgrowth.
Figure 4: Molecular codes for the generation of mdDA neurons.

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Acknowledgements

We would like to thank F. Jacobs, S. Smits and J. Pasterkamp for critical reading of the manuscript.

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  1. Department of Molecular Neuroscience, Utrecht University, The Netherlands

    Marten P. Smidt & J. Peter H. Burbach

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DATABASES

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Parkinson's disease

schizophrenia

FURTHER INFORMATION

Smidt's laboratory

Rudolf-Magnus Institute

Glossary

Notochord

A cord-like structure of mesodermal origin positioned ventrally in the embryo, directly underlying the neural tube. Later in development this structure becomes the vertebral column.

Floor plate

The ventral-most longitudinal subdivision of the neural tube of the midbrain and the spinal cord, which acts as a local signalling centre.

Basal plate

A longitudinal subdivision of the neural tube, lying between the floor plate and the alar plate.

Alar plate

A longitudinal subdivision of the neural tube, lying between the basal plate and the roof plate.

Roof plate

The dorsal-most longitudinal subdivision of the neural tube.

Ventricular zone

A cell layer positioned inside the neural tube, forming the ventricular walls, in which cell divisions that build the developing brain in an inside-out manner take place.

Radial migration

Migration of neurons along radial glia.

Tangential migration

Non-radial neuronal migration, which intersects the radial glia.

Proteoglycans

A class of proteins that are heavily glycosylated.

In ovo electroporation

Technique for gene transfer in developing chicks.

Choreic movement

Clinical condition in which movement control fails, leading to involuntary spasms.

Patch

A small circumscribed area differing from the surrounding area, as described in an anatomically regular pattern in the striatum.

Matrix

A region filled with a regular form of shapes, found as an anatomical landmark in the striatum.

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Smidt, M., Burbach, J. How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci 8, 21–32 (2007). https://doi.org/10.1038/nrn2039

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