Intrinsic Determinants of Axon Regeneration

Abstract

The failure of axons to regenerate in the damaged mammalian CNS is the main impediment to functional recovery. There are many molecules and structures in the environment of the injured nervous system that can inhibit regeneration, but even when these are removed or replaced with a permissive environment, most CNS neurons exhibit little regeneration of their axons. This contrasts with the extensive and vigorous axon growth that may occur when embryonic neurons are transplanted into the adult CNS. In the peripheral nervous system the axons usually respond to axotomy with a vigorous regenerative response accompanied by a regenerative programme of gene expression, usually referred to as the Regeneration-associated gene (RAG) program. These different responses to axotomy in the mature and immature CNS and the PNS lead to the concept of the intrinsic regenerative response of axons. Analysis of the many mechanisms and issues that affect the intrinisic regenerative response is the topic of this special issue of Developmental Neurobiology. The review articles highlight the control of expression of growth and regeneration-associated genes, emphasizing the role of epigenetic mechanisms. The reviews also discuss changes within axons that lead to the developmental loss of regenerative ability. This is caused by changes in axonal transport and trafficking, in the cytoskeleton and in signalling pathways. Axons and neurons are not all the sameWhether or not regeneration will occur after axotomy depends on the type of axon that is cut and where along its length. Axons in peripheral nerves, whether sensory, Correspondence to: J. Fawcett (jf108@cam.ac.uk)

Comparative gene expression profiling reveals the mechanisms of axon regeneration

“…By using comparative gene expression profiling, the mechanisms of axon regeneration have been studied in the last few decades and many new molecular targets have been identified. Many studies have contributed to making a list of Accepted Article genes as a "regeneration-associated genes, RAGs" that are regulating the specific steps of axon regeneration [15,67,85,[94][95][96]. From the identified RAGs, the functional relationships and physiological relevance of the differentially regulated RAGs in regeneration need to be investigated in the future [66].…”

Molecular basis of the functions of the mammalian neuronal growth cone revealed using new methods

“…Intrinsic inhibitory mechanisms for limiting the maintenance of growth cone activity are present in the adult brain, and approaches for removing these factors have led to partially successful axon regeneration. 192,193) Such mechanisms are generally energy-consuming, and maintaining them at an adult stage will be disadvantageous for energy economics in the mammalian brain, which has a large number of neurons.…”

Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration

“…Injured axons in the adult mammalian central nervous system (CNS) generally cannot regenerate over long distances, limiting functional recovery from CNS injury (1). Potential mechanisms underlying regenerative failure in the mature CNS include a lack of an intrinsic ability to activate genes and pathways required for axon regrowth after injury (2,3); the presence of extrinsic growth-repulsive factors associated with certain extracellular matrix molecules, myelin debris, or fibrotic tissue (4)(5)(6); and limited availability of appropriate growth factors (1, 7,8). Strategies to neutralize or attenuate key cell-extrinsic inhibitors of axon growth have limited effects on regeneration (9,10), though their impact is strongly enhanced by co-activating neurons' intrinsic growth state (11)(12)(13).…”