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Molecular mechanisms of dopaminergic subset specification: fundamental aspects and clinical perspectives

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Abstract

Dopaminergic (DA) neurons in the ventral mesodiencephalon control locomotion and emotion and are affected in psychiatric and neurodegenerative diseases, such as Parkinson’s disease (PD). A clinical hallmark of PD is the specific degeneration of DA neurons located within the substantia nigra (SNc), whereas neurons in the ventral tegmental area remain unaffected. Recent advances have highlighted that the selective vulnerability of the SNc may originate in subset-specific molecular programming during DA neuron development, and significantly increased our understanding of the molecular code that drives specific SNc development. We here present an up-to-date overview of molecular mechanisms that direct DA subset specification, integrating our current knowledge about subset-specific roles of transcription factors, signaling pathways and morphogenes. We discuss strategies to further unravel subset-specific gene-regulatory networks, and the clinical promise of fundamental knowledge about subset specification of DA neurons, with regards to cell replacement therapy and cell-type-specific vulnerability in PD.

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Abbreviations

CNS:

Central nervous system

DA:

Dopaminergic

DOPAC:

Dihydroxyphenylacetic acid

DOPAL:

Dihydroxyphenylacetaldehyde

ESCs:

Embryonic stem cells

FACS:

Fluorescence-activated cell sorting

GABA:

Gamma-aminobutyric acid

GFP:

Green fluorescent protein

iPSCs:

Inducible pluripotent stem cells

IsO:

Isthmic organizer

mdDA:

Mesodiencephalic dopaminergic

miRNA:

microRNA

GRN:

Gene-regulatory network

MHB:

Mid-hindbrain border

P1/2/3:

Prosomere 1/2/3

PD:

Parkinson’s disease

R3/5:

Rhombomere 3/5

RA:

Retinoic acid

SCs:

Stem cells

SNc:

Substantia nigra, pars compacta

TF:

Transcription factor

VTA:

Ventral tegmental area

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Acknowledgments

This work was supported by a VICI-ALW grant [865.09.002 to M.P.S.] from the Dutch Organisation for Scientific Research (NWO).

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  1. Department of Molecular Neuroscience, Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands

    Jesse V. Veenvliet & Marten P. Smidt

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  1. Jesse V. Veenvliet
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  2. Marten P. Smidt
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Correspondence to Marten P. Smidt.

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Veenvliet, J.V., Smidt, M.P. Molecular mechanisms of dopaminergic subset specification: fundamental aspects and clinical perspectives. Cell. Mol. Life Sci. 71, 4703–4727 (2014). https://doi.org/10.1007/s00018-014-1681-5

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  • DOI: https://doi.org/10.1007/s00018-014-1681-5

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