The role of transcription in axonal outgrowth and regeneration

Trauma in the adult mammalian central nervous system leads to irreversible structural and functional impairment due to failed regeneration attempts. In contrast, neurons in the peripheral nervous system exhibit a greater regenerative ability. It has been proposed that an orchestrated sequence of transcriptional events controlling the expression of specific sets of genes may be the underlying basis of an early cell-autonomous regenerative response. Understanding whether transcriptional fine tuning, in parallel with strategies aimed at counteracting extrinsic impediments promotes axon re-growth following central nervous system injuries represents an exciting challenge for future studies. Transcriptional pathways controlling axon regeneration are presented and discussed in this review.

The regenerative capacity of injured neurons in the central nervous system is limited due to the absence of a robust neuron-intrinsic injury-induced gene response that supports axon regeneration. In peripheral neurons axotomy induces a large cohort of regeneration-associated genes (RAGs). The forced expression of some of these RAGs in injured neurons has some beneficial effect on axon regeneration, but the reported effects are rather small. Transcription factors (TFs) provide a promising class of RAGs. TFs are hubs in the regeneration-associated gene network, and potentially control the coordinate expression of many RAGs simultaneously. Here we discuss the use of combined experimental and computational methods to identify novel regeneration-associated TFs with a key role in initiating and maintaining the RAG-response in injured neurons. We propose that a relatively small number of hub TFs with multiple functional connections in the RAG network might provide attractive new targets for gene-based and/or pharmacological approaches to promote axon regeneration in the central nervous system.