O'Neill, Paul; (2002) Developmental regulation of regenerative potential in the spinal cord. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Injury to the adult central nervous system cannot be effectively repaired, leading to chronic disability. In contrast, embryonic neurons possess extensive regenerative capabilities, permitting functional recovery after axonal damage. The embryonic chick can functionally recover from spinal injury at developmental stages prior to embryonic day 13, at which point the CNS undergoes transition from a permissive to restrictive environment for neuronal regeneration. The developmentally regulated molecular changes responsible for this transition remain to be fully characterised: the principle aim of this study was to advance understanding in this area. A number of markers have been investigated, using immunohistochemistry, RT-PCR, and Western Blotting to establish the contribution of neuronal and glial populations to the failure of regeneration in the embryonic chick and human. In addition, the relative contributions of primary and secondary tissue damage following spinal injury have been addressed by measuring the extent and duration to which apoptosis occurs during permissive or restrictive stages of development. The major findings of this research are that; 1.) Cell death following injury, particularly due to secondary injury mechanisms, plays a crucial, and perhaps principal role in establishing a non-permissive CNS environment during the restrictive period for regeneration: 2.) The myelin-associated inhibitor of neurite outgrowth, Nogo-A, and its receptor, do not contribute majorly to the transition from permissive to restrictive states during development, and seems to play an important, previously un-described, role during embryogenesis; 3.) Elevated levels of chondroitin sulphate proteoglycans through development, in addition to altered cellular localisation, are likely to contribute to the overall non-permissiveness of the mature spinal cord. To conclude, this study has clarified some of the issues concerning the generation of a non-permissive environment during development in the embryonic chick and human, and has laid foundation for further research concerning the novel role of Nogo proteins during embryogenesis.

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