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Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF.
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Exp Neurol 2013 Oct;
Authors: C Zhang, Y Jin, K S Ziemba, A M Fletcher, B Ghosh, E Truit, D M Yurek, G M Smith
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, USA.
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 ?1 (GFR?-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?-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?-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.
PMID: 24099728 [PubMed - as supplied by publisher]