Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Abstract

Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low ability of many CNS neurons to mount an effective regenerative growth response. To improve outcomes, it is essential to understand and ultimately reverse these neuron-intrinsic constraints. Genetic manipulation of key transcription factors (TFs), which act to orchestrate production of multiple regeneration-associated genes, has emerged as a promising strategy. It is likely that no single TF will be sufficient to fully restore neuron-intrinsic growth potential, and that multiple, functionally interacting factors will be needed. An extensive literature, mostly from non-neural cell types, has identified potential mechanisms by which TFs can functionally synergize. Here we examine four potential mechanisms of TF/TF interaction; physical interaction, transcriptional cross-regulation, signaling-based cross regulation, and co-occupancy of regulatory DNA. For each mechanism, we consider how existing knowledge can be used to guide the discovery and effective use of TF combinations in the context of regenerative neuroscience. This mechanistic insight into TF interactions is needed to accelerate the design of effective TF-based interventions to relieve neuron-intrinsic constraints to regeneration and to foster recovery from CNS injury.

Intrinsic mechanisms of neuronal axon regeneration

“…In addition to the previously highlighted transcription factors, several others — namely Myc proto-oncogene protein (MYC) 137 , hypoxia-inducible factor 1α (HIF1α) 138 , CREB1 (REFS 36,113 ), SOX11 (REFS 139–143 ), TP53 (REFS 46,144 ), SRF48,145 and XBP1 (REFS 90,91 ) — have been identified to have roles in axon regeneration (see TABLE 1 and REFS 146,147 ). As little is known about the mechanisms by which these transcription factors are activated after injury, their regulation during development or their downstream targets, they will not be further discussed in detail here.…”

“…Genetic manipulations that have focused on overexpression of regeneration-associated genes or transcription factors have yielded limited success 114,143,146,148 . This lack of success could be because more than one factor is necessary to fully stimulate the growth process; however, another explanation is that the cellular context dictates the competency of the neurons to respond to a given genetic manipulation.…”

Can injured adult CNS axons regenerate by recapitulating development?

“…In most cases, transcription factors have been tested singularly for roles in regeneration. However, bioinformatic approaches have recently determined functional interactions between pathways involved in axonal outgrowth and may reveal transcription factor combinations that can optimize regeneration (Belin et al, 2015;Chandran et al, 2016;Venkatesh and Blackmore, 2016).…”

Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

“…Using this model system, many intrinsic signaling pathways involved in axon regeneration have been identified (4,(8)(9)(10)(11). A major focus has been on revealing the regenerative-associated genes (RAGs) promoting axon regeneration (1,12,13) and the coordinated regulation of such genes (14,15). However, the roles and the epigenetic mechanisms by which genes are repressed after injury remain poorly understood.…”