Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF

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 gr...

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Published in:	Experimental neurology Vol. 250; pp. 156 - 164
Main Authors:	Zhang, C., Jin, Y., Ziemba, K.S., Fletcher, A.M., Ghosh, B., Truit, E., Yurek, D.M., Smith, G.M.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Inc 01-12-2013 Elsevier
Subjects:	Animals Axonal guidance Axons - physiology Biological and medical sciences Blotting, Western Brain Tissue Transplantation - methods Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Dopaminergic Neurons - transplantation Female GDNF Glial Cell Line-Derived Neurotrophic Factor - metabolism Humans Immunohistochemistry Injuries of the nervous system and the skull. Diseases due to physical agents Lentivirus Medical sciences Mesencephalon - transplantation Mice Nerve Growth Factors - metabolism Nervous system (semeiology, syndromes) Nervous system as a whole Netrin-1 Neurology Parkinson's disease Rats Rats, Sprague-Dawley Transfection Traumas. Diseases due to physical agents Tumor Suppressor Proteins - metabolism Tyrosine hydroxylase Ventral mesencephalon (VM) transplantation Parkinson's disease GDNF Netrin-1 Axonal guidance Tyrosine hydroxylase Lentivirus Ventral mesencephalon (VM) transplantation Growth Parkinson disease Transplantation Tyrosine 3-monooxygenase Surgery Glial cell line derived neurotrophic factor Graft Degenerative disease Dopaminergic pathway Nervous system diseases Enzyme Retroviridae Axon Cerebral disorder Virus Guidance Treatment Central nervous system disease Oxidoreductases Extrapyramidal syndrome
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Summary:	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 α1 (GFRα-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 GFRα-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/GFRα-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. •Little is known of what factors mediate the growth of dopaminergic axons in the adult brain.•We examined factors that induced unidirectional growth of transplanted dopamine neurons.•GDNF, GFR-α1, and netrin-1 supported some long distance growth in the adult brain.•Combinations of GDNF/GFR-α1 or GDNF/netrin-1 supported robust growth over long distances.•Such factors could be used to reconstruct the nigrostriatal pathway in Parkinson's models.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0014-4886 1090-2430
DOI:	10.1016/j.expneurol.2013.09.022