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Roles for the TGFβ Superfamily in the Development and Survival of Midbrain Dopaminergic Neurons

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Abstract

The adult midbrain contains 75 % of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct clusters termed A8, A9 and A10. The A9 group plays a functionally non-redundant role in the control of voluntary movement, which is highlighted by the motor syndrome that results from their progressive degeneration in the neurodegenerative disorder, Parkinson’s disease. Despite 50 years of investigation, treatment for Parkinson’s disease remains symptomatic, but an intensive research effort has proposed delivering neurotrophic factors to the brain to protect the remaining dopaminergic neurons, or using these neurotrophic factors to differentiate dopaminergic neurons from stem cell sources for cell transplantation. Most neurotrophic factors studied in this context have been members of the transforming growth factor β (TGFβ) superfamily. In recent years, an intensive research effort has focused on understanding the function of these proteins in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region, with the goal of applying this knowledge to develop novel therapies for Parkinson’s disease. In this review, the current evidence showing that TGFβ superfamily members play critical roles in the regulation of midbrain dopaminergic neuron induction, differentiation, target innervation and survival during embryonic and postnatal development is analysed, and the implications of these findings are discussed.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

ALK:

Activin receptor-like kinases

BDNF:

Brain-derived neurotrophic factor

BMP:

Bone morphogenetic protein

BMPR:

BMP receptors

Co-Smads:

Common mediator Smads

DA:

Dopaminergic/dopamine

E:

Embryonic day

FGF:

Fibroblast growth factor

GDF:

Growth/differentiation factor

GDNF:

Glial cell line-derived neurotrophic factor

I-Smads:

Inhibitory Smads

MPP+:

1-Methyl-4-phenylpyridinium ion

P:

Postnatal day

PD:

Parkinson’s disease

R-Smads:

Receptor-regulated Smads

Shh:

Sonic hedgehog

TGFβ:

Transforming growth factor β

TH:

Tyrosine hydroxylase

VM:

Ventral midbrain/mesencephalon

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Acknowledgments

Work in the authors’ laboratories is supported by grants from the Irish Research Council (R13702; SVH/AS/G’OK), the Health Research Board of Ireland (HRA/2009/127; GO’K/AS) and Science Foundation Ireland (10/RFP/NES2786; GO’K).

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  1. Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland

    Shane V. Hegarty, Aideen M. Sullivan & Gerard W. O’Keeffe

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  1. Shane V. Hegarty
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  2. Aideen M. Sullivan
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  3. Gerard W. O’Keeffe
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Correspondence to Aideen M. Sullivan or Gerard W. O’Keeffe.

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Aideen Sullivan and Gerard O’Keeffe contributed equally to this work.

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Hegarty, S.V., Sullivan, A.M. & O’Keeffe, G.W. Roles for the TGFβ Superfamily in the Development and Survival of Midbrain Dopaminergic Neurons. Mol Neurobiol 50, 559–573 (2014). https://doi.org/10.1007/s12035-014-8639-3

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