The role of retrograde repression in limiting axonal regeneration in the central nervous system
The regenerative capacity of mature mammalian CNS neurons after axonal injury is severely limited by a variety of mechanisms. Retrograde repression is the continuous inhibition of the expression of growth phenotypes by tonic signals produced by target tissues and transmitted to the neuron cell body via retrograde axonal transport. Loss of target contact through axonal injury is thought to interrupt this retrograde signal and allow the up-regulation of growth-associated proteins. Most CNS neurons, however, possess many widespread axon collaterals, such that retrograde repression is maintained by intact sustaining collaterals even if some axons are injured.In this project we investigated whether or not retrograde repression plays a role in limiting the expression of GAP-43 in transcallosal neurons. Because TCNs possess local axon collaterals to nearby cortex and project distal axons to homologous areas of contralateral cortex, we hypothesized that the simultaneous interruption of retrograde repressive signals from both ipsilateral and contralateral cortex would result in an up-regulation of GAP-43 expression in at least some TCNs.We found that a bilateral infusion of a function blocking antibody to FGF-2 into the parietal cortex of rats using implanted osmotic mini-pumps resulted in a significant increase in the level of expression of GAP-43 mRNA in TCNs identified by retrograde fluorescent labeling. In contrast, neither ipsilateral or contralateral antibody infusions alone increased GAP-43 expression significantly compared to controls. The level of expression of GAP-43 in TCNs did not significantly increase after stereotactic callosotomy alone, but callosotomized animals treated with an ipsilateral infusion of anti-FGF-2 had levels of increased GAP-43 expression equivalent to those seen in animals that had received bilateral antibody infusions.We conclude that FGF-2 provides a retrograde repressive signal for at least some mature mammalian TCNs, and that the expression of growth-associated proteins can be up-regulated in CNS neurons by simultaneously blocking retrograde repressive signals from all existing axon collaterals. The ability to alter the gene expression of mature CNS neurons in both normal and injured states through the targeted infusion of a pharmacological agent may have potential clinical implications in the future.
Retrograde repression, axon regeneration, central nervous system, GAP-43, FGF-2
Master of Science (M.Sc.)