SGER: Does Re-expression of Vimentin Induce Resumption of Axonal Elongation?

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Neurons, extend long processes called axons, that act essentially as telephone wires and transmit the signals that allow us to think, feel and move. During embryonic development, axons elongate at a rapid rate, connecting nerve cells and muscles. Once an axon reaches its target, however, it stops elongating and stabilizes its structure, since its task is now to remain connected for the lifetime of the individual. The axon is supported internally by a series of fibrous structures collectively referred to as the cytoskeleton (that is, the skeleton of the cell). Dr. Shea's laboratory has shown that the rapid elongation during development is mediated by a protein called vimentin, that forms pliable filaments that rapidly assemble and disassemble. Once the neuron reaches its target, however, it stops producing vimentin, and replaces it with a different group of proteins called neurofilaments. Neurofilaments make fibers that cross link and bind together, and form a stabilized matrix that supports the now fully-grown axon. Unfortunately, should an axon die or be severed, the portion that is connected to the neuron is unable to start growing again to allow reconnection to its previous target. The PI has studied these events in neuroblastoma cells; a cell line, due to ease of manipulation and cost-effectiveness. Their early observations indicated a developmental heirarchy in intermediate filaments (IFs). Vimentin (Vm) is the predominant IF species during axonal initiation. During axonal elongation, Vm expression ceases and neurons express neurofilament (NF) proteins, which increase axonal caliber and stabilize the developing axon. Dr. Shea's laboratory has demonstrated by intracellular delivery of neutralizing antibodies and antisense oligonucleotides that Vm is essential for axon initiation but is dispensable once the axon has formed; conversely, NFs are not required for axonal initiation but are essential for axonal stabilization. The PI proposes to examine further this phenomenon in motor neurons (neurons that connect to and stimulate muscle cells) grown outside the body, to determine whether or not we can induce axons to start growing again and whether or not such axons stop growing when they reach their targets. Dr. Shea's laboratory is proficient in all of the required methodologies, and this project will provide rich training opportunities for graduate and undergraduate students.