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

C. Zhang, Y. Jin, K. S. Ziemba, A. M. Fletcher, B. Ghosh, E. Truit, D. M. Yurek, G. M. Smith

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)156-164
Number of pages9
JournalExperimental Neurology
Volume250
DOIs
StatePublished - Dec 2013

Bibliographical note

Funding Information:
This work was funded by grants from the National Institute of Neurological Disorders and Stroke with numbers R01 NS060784 (GMS), NS050311 and NS075871 (DMY) and from the Shriners Hospital for Pediatric Research grants SHC 84050 and SHC 85200 (GMS).

Keywords

  • Axonal guidance
  • GDNF
  • Lentivirus
  • Netrin-1
  • Parkinson's disease
  • Tyrosine hydroxylase
  • Ventral mesencephalon (VM) transplantation

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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