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 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.
O'Keeffe
Gráinne C
GC
Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom.
Tyers
Pam
P
Aarsland
Dag
D
Dalley
Jeffrey W
JW
Barker
Roger A
RA
Caldwell
Maeve A
MA
D000375:Aging / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D004298:Dopamine