Collaborative Research: Role of Neurofilament Transport in the Growth of Axonal Caliber

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Nerve cells communicate by conducting electrical signals along slender cytoplasmic extensions known as axons. Animals have evolved two basic mechanisms for increasing axonal conduction velocity. One is to increase axonal diameter and the other is to insulate axons by a process called myelination, which is a tight spiral wrapping of the axons that is formed by myelinating cells. In vertebrates the growth of axon diameter is caused principally by the accumulation of space-filling cytoskeletal polymers called neurofilaments inside the axons, and this is regulated locally by chemical signals from the myelinating cells. It is known that neurofilaments are transported along axons and that they alternate between rapid movements and prolonged pauses. The proportion of the time that the neurofilaments spend pausing is likely to be a principal determinant of their residence time in axons. This is a collaborative experimental and modeling project involving a biologist at Ohio State University and a physicist at Ohio University. The central hypothesis to be tested is that myelinating cells control axonal caliber by regulating neurofilament pausing. A computational model will be developed that relates the moving and pausing behavior of neurofilaments to their distribution along axons. The model will be based on detailed kinetic parameters of neurofilament movement derived experimentally in cultured neurons and will be verified experimentally by fluorescence microscopy of neurofilament movement in myelinated axons in tissue culture. The proposed research will generate a rigorous and quantitative framework that relates the size and shape of axons, which is a key influence on their electrical properties, to the moving and pausing behavior of their internal constituents. The research will involve graduate and undergraduate students in both the physical and biological sciences, providing an integrated and cross-disciplinary training experience at the interface between computational and experimental biology.