Figure 1.

Regeneration-associated gene networks. Axonal injury activates many signal transduction pathways that can lead to gene transcription. The upregulation of cAMP levels after injury is important for RAG expression, serving to activate CREB, AP1, and possibly other transcription factors in parallel. These transcription factors can serve as hub proteins (in yellow circles) to control the transcription of terminal RAGs (in gray circles) that may serve related physiological functions. Some hub proteins, such as CREB, drive the transcription of other hub proteins. In this case, AP1 subunits and ATF3 are direct CREB target genes. As such, CREB is a highly connected node of the RAG transcription network and serves to coordinate the transcription of many terminal RAGs through their proximal hub proteins. These highly connected nodes are attractive therapeutic targets that can recapitulate more of the RAG response and can be targeted by viral-mediated gene delivery (i.e., constitutive-active CREB, virus cartoon). Additionally, injury-induced signals may also work locally and interact with the protein products of the transcribed RAGs to augment axon growth. Thus, strategies that increase/induce RAG expression along with activation of injury signals (i.e., cAMP, syringe and pill cartoon) may show synergy in promoting axon regeneration.