Cellular and molecular correlates of the regeneration of adult mammalian CNS axons into peripheral nerve grafts

Abstract

Studies of the regeneration of CNS axons into peripheral nerve grafts have provided information crucial to our understanding of the regenerative potential of CNS neurons. Injured axons in the thalamus and corpus striatum produce regenerative sprouts within a few days of graft implantation, apparently in response to living cells in the grafts. The regenerating axons often grow directly towards the grafts, and enter Schwann cell columns where they elongate surrounded by Schwann cell processes. The regenerating CNS axons, and the Schwann cell processes along which they grow, initially express the cell adhesion molecules NCAM, and L1. The axons also express polysialic acid and, unlike regenerating peripheral axons, bind tenascin-C derived from Schwann cells. Wherever peripheral nerve grafts are implanted into the CNS they appear to promote the differential regeneration of CNS axons. Most of the axons which grow into grafts in the thalamus are derived from the thalamic reticular nucleus (TRN), whereas grafts in the striatum promote regeneration of axons from the substantia nigra pars compacta (SNpc) and grafts in the cerebellum promote regeneration from deep cerebellar nuclei (DCN) and brainstem precerebellar neurons. In contrast most thalamocortical projection neurons, striatal projection neurons and Purkinje cells in the cerebellar cortex are poor at regenerating. There are patterns to the expression of regeneration-related molecules by axons injured by nerve grafts in the CNS. Most neurons which regenerate well (e.g. TRN and DCN neurons) upregulate GAP-43, L1 and the transcription factor c-jun in response to a graft, whereas those neurons which do not regenerate well (e.g. Purkinje cells, thalamocortical and striatal projection neurons) do not upregulate these molecules. These observations suggest that some classes of CNS neurons may be intrinsically unable to regenerate axons and the repair of injuries in the brain and spinal cord may consequently require some form of gene therapy for axotomised neurons.