SLOW AXONAL TRANSPORT IN CNS DEVELOPMENT

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The delivery of cytoskeletal proteins by slow axonal transport is known to have an essential role in axonal growth but our present information on the details of this process in developing CNS axons in mammals is extremely limited. Additionally, we presently know almost nothing about the synthesis and transport of axonal cytoskeletal and cytomatrix proteins during the response to injury in mammalian CNS axons. An ideal CNS system for studying these issues is the corticospinal tract of the hamster. Hamster corticospinal axons arise from the motor cortex, innervate all segments of the spinal cord, and develop predominantly postnatally. Futhermore, in the immature animal, these axons exhibit remarkable plasticity, and have been shown to undergo some regrowth after injury. Thus, axons of this system can be examined during initial development, during a period when they maintain a capacity for regrowth, and in maturity. The proposed studies will first examine changes in the parameters of slow axonal transport that occur during normal development and maturation of these axons, and then determine how injury affects these parameters. Proteins transported with the slow components of axonal transport, SCa and SCb) (including actin, tubulin, neurofilament proteins, microtubule-associated proteins, actin-associated proteins, and a number of other proteins) will be selectively labelled by injecting radiolabelled amino acids into the motor cortex and harvested after they enter axons via slow axonal transport. Gel electrophoresis and fluorography will be used to biochemically characterize changes in the axonal cytoskeleton and assess changes in the rate of transport of cytoskeletal and associated proteins during development. Heterogeneity of axonal cytoskeletal proteins and quantitative changes in major slowly transported proteins will be examined during development and after injury. By defining in a careful and quantitative manner the detailed changes in the biochemistry and dynamics of the axonal cytoskeleton in CNS axons, important advances in our understanding of the mechanisms which influence the regenerative capacity of the neuron will be made.