Central nervous system development and injury: Characterization of cytoskeletal gene expression in neurons and glia

Injury to the nervous system provokes a number of molecular alterations in both neurons and glia. Many investigators have examined the axotomy response of peripheral neurons which have the ability to regenerate their axons giving particular attention to the structural proteins that comprise the cytoskeleton. While it is an unfortunate reality that central nervous system (CNS) neurons do not effectively regrow after injury, surprisingly little is known about their response to injury. This thesis examined neuronal and glial changes in cytoskeletal gene expression after transection of a major CNS tract in the adult hamster. In situ hybridization was used to examine changes in alpha tubulin and neurofilament gene expression in corticospinal neurons after transection in the caudal medulla. The results demonstrated that tubulin gene expression decreased after axotomy--a finding never before observed after neuronal injury, and a decreased neurofilament gene expression--a finding similar to those in peripheral neurons after axotomy. Changes in glial fibrillary acidic protein and vimentin mRNA within astrocytes located in the degenerating part of the tract were also examined and a dramatically increased expression of both GFAP and vimentin mRNA was observed. These findings demonstrate that the CNS molecular "regeneration program" is intrinsically different from that in peripheral neurons, and that astrocytes robustly respond to CNS injury.; While not fully understood, it is a widely accepted phenomenon that developing CNS neurons exhibit considerable plasticity. Interestingly, it has been hypothesized that a developmental program of cytoskeletal gene expression is recapitulated during regeneration. However, developmental patterns of major cytoskeletal genes have not been examined in brain in one species. Therefore, this thesis examined the expression of intermediate filament, tubulin and microtubule-associated protein mRNAs during normal hamster brain development using northern blots. Because corticospinal neurons injured during early development are able to regrow their axons, this thesis examined alpha-tubulin gene expression after corticospinal axotomy in developing hamsters. Similar to the adult injury response, a decrease in tubulin gene expression was observed but a different time course of change in the immature animal was found. This suggests that the developmental program of expression influences the regenerative ability of corticospinal neurons.