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

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.

Postinjury Induction of Activated ErbB2 Selectively Hyperactivates Denervated Schwann Cells and Promotes Robust Dorsal Root Axon Regeneration

“…We observed that post-injury induction of caErbB2 similarly stimulates SCs in injured DRs to proliferate and form processes and delays their re-dedifferentiation. Our findings are consistent with the notion that NRG-1/ErbB signaling may initiate SC dedifferentiation after injury (C. Zhang et al, 2013;Lee et al, 2014).…”

“…Replication deficient lentiviruses encoding either chABC (LVchABC) or GDNF (LV-GDNF) used a pBOB lentiviral expression vector with CMV-enhanced chicken ␤-actin (CAG) promoter. The procedures to generate the viruses and their efficacy were described previously; LVchABC (Curinga et al, 2007;Jin et al, 2011) and LV-GDNF (L. Deng et al, 2013;C. Zhang et al, 2013;Kelamangalath et al, 2015).…”

“…When expressed virally within the spinal cord, GDNF enhances intraspinal regeneration of largediameter DR axons (Deng et al, 2013;C. Zhang et al, 2013;Kelamangalath et al, 2015).…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…In addition to its action on DA neuron survival, GDNF also stimulates outgrowth of DA neurons after lesion or grafting in the rodent (Sinclair et al, 1996;Sautter et al, 1998;Wilby et al, 1999;Zhang et al, 2013) and NHP brain Redmond Jr. et al, 2009;Wakeman et al, 2014). Combination of GDNF and NETRIN-1 was found to support directed long-distance growth of DA axons from rodent fVM grafts .…”

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

“…These GABAergic transplants into the nigra also may contribute benefit by increasing the local suppression of noise as described previously for the seemingly noisy striatum. As efforts expanded, it became clear that considerable neurotrophic support was necessary and this was either provided by "bridge" tissue grafts that might be likely to release such compounds, such as Schwann cell type cells, or the local cells were induced to release these compounds by viral transgenic expression (e.g., [82,160,170]). This strategy renders the CNS territory through which the new dopaminergic fibers must grow more hospitable, presumably also providing retrograde support signals, inspiring continued growth, and staving off the previously-described cell death that results from the lack of connectedness during this growth journey.…”