Journal
EXPERIMENTAL NEUROLOGY
Volume 250, Issue -, Pages 156-164Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2013.09.022
Keywords
Axonal guidance; Ventral mesencephalon (VM) transplantation; GDNF; Netrin-1; Lentivirus; Tyrosine hydroxylase; Parkinson's disease
Categories
Funding
- National Institute of Neurological Disorders and Stroke [R01 NS060784, NS050311, NS075871]
- Shriners Hospital for Pediatric Research [SHC 84050, SHC 85200]
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Different experimental and clinical strategies have been used to promote survival of transplanted embryonic ventral mesencephalic (VM) neurons. However, few studies have focused on the long-distance growth of dopaminergic axons from VM transplants. The aim of this study is to identify some of the growth and guidance factors that support directed long-distance growth of dopaminergic axons from VM transplants. Lentivirus encoding either glial cell line-derived neurotrophic factor (GDNF) or netrin-1, or a combination of lenti-GDNF with either lenti-GDNF family receptor alpha 1 (GFR alpha-1) or lenti-netrin-1 was injected to form a gradient along the corpus callosum. Two weeks later, a piece of embryonic day 14 VM tissue was transplanted into the corpus callosum adjacent to the low end of the gradient. Results showed that tyrosine hydroxylase (TH+) axons grew a very short distance from the VM transplants in control groups, with few axons reaching the midline. In GDNF or netrin-1 expressing groups, more TH+ axons grew out of transplants and reached the midline. Pathways co-expressing GDNF with either GFR alpha-1 or netrin-1 showed significantly increased axonal outgrowth. Interestingly, only the GDNF/netrin-1 combination resulted in the majority of axons reaching the distal target (80%), whereas along the GDNF/GFR alpha-1 pathway only 20% of the axons leaving the transplant reached the distal target. This technique of long-distance axon guidance may prove to be a useful strategy in reconstructing damaged neuronal circuits, such as the nigrostriatal pathway in Parkinson's disease. (C) 2013 Elsevier Inc. All rights reserved.
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