The role of Cited2 in axonal regeneration

Abstract

Neuronal maturation is characterised as the switch from a neuronal growth to a synapse formation stage and is accompanied by a decreasing neuronal regenerative capacity during development that continues throughout age. A spinal cord injury results in the failure to activate a regenerative programme in mature adult neurons, critically limiting regeneration and functional recovery. Whether neuronal maturation marks the decline in growth competence in the injured mammalian adult nervous system remains elusive. Resulted indicated that gene expression and epigenetic signatures associated with regenerative growth of dorsal root ganglia sensory neurons are lost throughout neuronal maturation and polarisation. The transcriptional co-factor Cited2 was identified and found to be epigenetically upregulated in immature non-polarised DRG neurons and after a regenerative peripheral injury, but not after a non-regenerative spinal cord injury. Overexpressing Cited2 promoted axonal regeneration, reversed gene expression and epigenetic signatures associated with neuronal maturation, and induced the transition towards an immature, non-polarised phenotype in DRG neurons. These results indicate that the transition to a mature state marks the reversible loss of the neuronal regenerative ability and can be manipulated, thus paving the way to targeted repair strategies relaying on neuronal dematuration.