Both short (across an injury site) and long distance growth (back to central visual targets) must be addressed and may involve separate signaling pathways. Considerable progress has been made in identifying candidate molecules that stimulate axons to grow across an optic nerve injury site.
5,6 Manipulation of local glial, vascular, and inflammatory responses all deserve additional attention, and testing combinatorial therapies and evaluating the quality of regenerative growth, including axon guidance, remain largely unexplored and should represent a major objective of the AGI. Indeed, the next major challenge is to encourage long distance growth to appropriate targets while minimizing aberrant growth and sprouting.
7,8 While much progress has been made to understand the mechanisms underlying guidance, target selection, and synapse formation of developing axons, little is known about how regenerating axons perform after injury.
6,9,10 Workshop participants generally dismissed the requirement that regenerative axon growth should necessarily recapitulate developmental patterning regarding pathway choice, target selection from the dozen different subcortical targets for regenerating RGCs to choose from,
11 or specificity of synaptic connectivity.
12 In regenerating axons, what steps need to be taken to prevent an aberrant projection from developing and innervating the spared/undamaged retina or inappropriate areas in the brain? Since target selection is cell-type specific, getting specific RGC types to innervate the appropriate target and become reintegrated into existing or remodeled circuits may be crucial, although questions on circuit reintegration in the adult are largely unstudied. Thus, it will be important to identify guidance cues and synapse formation signaling pathways in a regenerative environment. Indeed, some axon growth–promoting regenerative therapies may introduce guidance or synapse formation problems, while others may not, suggesting that all regenerative therapies may not be equal. Within this context, however, there was discussion that RGC innervation of brain targets subserving image formation may be more important than promoting regeneration of RGCs dedicated to non–image-forming functions such as pupillary light response or photoentrainment of circadian rhythm.