| Axons in the spinal cord of adult birds and mammals are unable to regenerate if they are severed by injury, so paralysis and loss of sensation are permanent. A major goal of neuroscience research is to identify and overcome the factors that limit axon regeneration. Unlike adults, embryonic animals do regenerate axons in the spinal cord, but lose this ability during a discrete developmental transition. This transition provides a point of entry into the problem of spinal cord injury. The basic strategy of my thesis work is to use the spinal cord of the embryonic chicken as a model to ask basic questions about how regeneration succeeds in the young spinal cord and why it fails in the adult. I first address the fundamental question of whether axon growth is limited more by the environment of the spinal cord or by the internal state of neurons, and demonstrate that changes in developing neurons are central to the failure of axon regeneration. I next examine a potential role for adhesion as a limiting factor in the regenerative capacity of older axons. I start by identifying three adhesive receptors, beta1 integrin, L1, and N-cadherin as critical to axon regeneration by younger neurons. I then rule out the hypothesis that a low expression of these receptors explains the poor regeneration by older neurons. Older neurons continue to express mRNA for beta1 integrin and L1, and expressing exogenous L1 in older neurons does not enhance their regenerative capacity. I do detect age-related differences in the post-translational modification of L1, so it is possible that older neurons have more subtle defects in L1 expression. In sum, my data point to important neuron-intrinsic changes that limit regeneration during development, and show that these changes are more fundamental than a decrease in the expression of adhesive receptors. |
