What makes a RAG regeneration associated? - PubMed (original) (raw)
Review
What makes a RAG regeneration associated?
Thong C Ma et al. Front Mol Neurosci. 2015.
Abstract
Regenerative failure remains a significant barrier for functional recovery after central nervous system (CNS) injury. As such, understanding the physiological processes that regulate axon regeneration is a central focus of regenerative medicine. Studying the gene transcription responses to axon injury of regeneration competent neurons, such as those of the peripheral nervous system (PNS), has provided insight into the genes associated with regeneration. Though several individual "regeneration-associated genes" (RAGs) have been identified from these studies, the response to injury likely regulates the expression of functionally coordinated and complementary gene groups. For instance, successful regeneration would require the induction of genes that drive the intrinsic growth capacity of neurons, while simultaneously downregulating the genes that convey environmental inhibitory cues. Thus, this view emphasizes the transcriptional regulation of gene "programs" that contribute to the overall goal of axonal regeneration. Here, we review the known RAGs, focusing on how their transcriptional regulation can reveal the underlying gene programs that drive a regenerative phenotype. Finally, we will discuss paradigms under which we can determine whether these genes are injury-associated, or indeed necessary for regeneration.
Keywords: cyclic AMP; injury conditioning; regeneration; regeneration associated genes; transcription factors.
Figures
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.
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