Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF

A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopami...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-05, Vol.106 (21), p.8754-8759
Main Authors: O'Keeffe, Gráinne C, Tyers, Pam, Aarsland, Dag, Dalley, Jeffrey W, Barker, Roger A, Caldwell, Maeve A
Format: Article
Language:English
Subjects:
Adult stem cells
Aging - physiology
Animals
B lymphocytes
Biological Sciences
Brain
Cell cycle
Cell Differentiation
Cell growth
Cell Proliferation - drug effects
Comparative analysis
Dopamine - pharmacology
Enzyme Activation
Epidermal Growth Factor - metabolism
Female
Mammals
Medicin och hälsovetenskap
Neural stem cells
Neurogenesis
Neurons
Neurons - cytology
Neurons - metabolism
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson's disease
Rats
Rats, Sprague-Dawley
Receptor, Epidermal Growth Factor - metabolism
Receptors
Stem cells
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Summary:A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP⁺ multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that EGFR⁺ cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.0803955106