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Brain Advance Access published online on January 17, 2008
Brain, doi:10.1093/brain/awm340
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Induction of A9 dopaminergic neurons from neural stem cells improves motor function in an animal model of Parkinson's disease

Fiona E. O’Keeffe1,2, Sarah A. Scott1, Pam Tyers1, Gerard W. O’Keeffe3, Jeffrey W. Dalley4,5, Romain Zufferey6 and Maeve A. Caldwell1,2

1Cambridge Center for Brain Repair and Department of Clinical Neurosciences, Forvie Site, Robinsons Way, Cambridge CB2 2PY, 2Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, Whitson St, Bristol, BS1 3NY, 3Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3US, 4Behavioral and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, 5Department of Psychiatry, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK and 6Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 15, CH-1015 Lausanne, Switzerland

Correspondence to: Maeve Caldwell, Henry Wellcome Laboratory for Intergrative Neurosciences & Endocrinology, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK E-mail: Maeve.Caldwell{at}bristol.ac.uk

Neural stem cells (NSCs) are widely endorsed as a cell source for replacement strategies in neurodegenerative disease. However, their usefulness is currently limited by the inability to induce specific neurotransmitter phenotypes in these cells. In order to direct dopaminergic neuronal fate, we overexpressed Pitx3 in NSCs that were then exposed to E11 developing ventral mesencephalon (VM) in explant culture. This resulted in a significant potentiation of dopaminergic differentiation of the cells. When transplanted into the 6-hydroxydopamine lesioned Parkinsonian rats, these cografts of VM and Pitx3 overexpressing NSCs resulted in a significant restitution of motor function. In addition, there were greater numbers of Girk2 positive A9 neurons in the periphery of the transplants that were NSC derived. This demonstrates that given the correct signals, NSCs can be induced to become dopaminergic neurons that can differentiate into the correct nigrastriatal phenotype required for the treatment of Parkinson's disease.

Key Words: Parkinson's disease; neural stem cells; transcription factors; dopamine neurons

Abbreviations: DA, dopaminergic; NPC, neural progenitor cells; NS, neurospheres; NSC, Neural stem cells; PD, Parkinson's disease; TH, tyrosine hydroxylase; VM, ventral mesencephalon

Received August 14, 2007. Revised December 19, 2007. Accepted December 24, 2007.


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