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Feng et al. Growth cone collapse in adult sensory neurons

of NGF, GDNF, and NT-3 caused the greatest increases
in growth cone collapse; conversely, when compared
with the pure EG-conditioned medium, inhibition of
BDNF did not appear to result in a significant increase
in growth cone collapse. This suggests that NGF,
GDNF, and NT-3 are the most important neurotrophic
factors in preventing or reversing SEMA3A-induced
collapse in the co-treatment setting.

In the post-treatment setting, inhibition of all
neurotrophic factors resulted in significant increases
in growth cone collapse when compared with the pure
EG-conditioned medium. This suggests that all the
neurotrophic factors in this study play an important role
in reversing SEMA3A-induced growth cone collapse
in a post-treatment setting. This particular setting is
unique in that it tests both inhibition and reversal of
growth cone collapse because it is the only time frame
where SEMA3A-induced collapse had already begun
before the EG-conditioned medium was introduced.
This may suggest why all 4 neurotrophic factors were
important in the post-treatment setting.

Previous studies have analyzed the combined effect
of neurotrophic factors on neuronal development and
regeneration in different settings. Madduri et al.
[36]
observed that NGF and GDNF work synergistically
in axon development; GDNF plays a greater role in
axon elongation while NGF plays a greater role in
axon branching. In another study that analyzed the
length of neurite outgrowth, the results demonstrated
that individual inhibition of BDNF and GDNF resulted
in decreased neurite length, but inhibition of both
neurotrophic factors resulted in the greatest reduction
in length. Furthermore, Hansebout et al. showed
[37]
[24]
that NGF, BDNF, GDNF, and NT-3 all play individual
roles in DRG neurite growth. In other SEMA3A models,
Figure 6: Images of DRG neurons from each sub-group in the post- Wanigasekara et al. found that SEMA3A-sensitive
[18]
treatment experiment. Each white bar represents 25 μm. DRG: neurons were heterogeneous in their expression
dorsal root ganglion
of NGF, GDNF, and neuritin receptors. Their study
settings. In fact, inhibition of BDNF in the co-treatment suggests that all of these factors have a role in axonal
setting did not cause a significant increase in collapse, and growth cone regeneration. Finally, Ben-Zvi et al.
[27]
suggesting a negligible role for BDNF in that time demonstrated that SEMA3A, NGF, BDNF, and NT-3
setting. Combined, these results suggest that while all play roles in determining whether DRG survive in
these neutrophic factors play large roles, none are mouse embryo models.
individually essential to the neuroprotective process.
The post-treatment model attempts to mimic the
The impact of each neurotrophic factor appears to clinical setting of post-trauma treatment of spinal
be variable. In the pre-treatment setting, inhibition of cord injury. Our study is novel in that it suggests the
BDNF or NT-3 resulted in the greatest increases in the entire complement of neurotrophins is necessary to
percentage of growth cone collapse when compared maximally reverse and prevent further insult to the
with the pure EG-conditioned medium. This suggests damaged area. However, no individual factor appears
that BDNF and NT-3 play the most important roles to be essential to the process. Since inhibition of each
in preventing SEMA3A-induced collapse in the pre- neurotrophic factor (NGF, BDNF, GDNF, NT-3) resulted
treatment setting. In the co-treatment setting, inhibition in an increase in growth cone collapse, it suggests EG
186 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ August 31, 2016