Collaborative Research: Dynamic Regulation of Axonal Morphology by Neurofilament Transport

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Nerve cells extend long, thin protrusions called axons that define the wiring pattern of the nervous system. Axons allow nerve cells to communicate electrically with each other and with other cells throughout the body. Each axon contains a microscopic, internal scaffold of space-filling proteins called neurofilaments that are constantly shuttled along the axon by molecular motor proteins; these define axon shape and size. Neurofilaments accumulate during development, increasing axon diameter and allowing electrical activity to travel more quickly; excessive accumulation (as occurs in many neurodegenerative diseases) can lead to communication abnormalities and axonal degeneration. This project tests the hypothesis that the rate of neurofilament transport determines the diameter, shape and function of axons. The work will be conducted by a seasoned interdisciplinary team of biologists and physicists, combining innovative biological imaging techniques with mathematical and computational methods to investigate these important questions. The insights gained from this research will be critical for understanding healthy brain function and could also provide important insights into the axonal problems observed in many neurodegenerative diseases. Trainees on this project from both the physical and life sciences will work in teams supervised by the principal investigators, and will expand their skills through interdisciplinary interaction, adding to the skilled research workforce at the interface of the physical and life sciences. To extend the impact of the proposed research to the K-12 level, the physicists and biologists on this project will host focused, small-group workshops that will seek to empower middle and high school teachers with ideas and tools to invigorate their instruction in the areas of cell biology and algorithmic thinking, and introducing freely available but powerful learning tools that they can apply in their classrooms.The function of nervous systems is dependent on the propagation of action potentials along axons at a velocity that is specific to their physiological function. This velocity is dependent on axon size and shape. A principal determinant of axon size and shape in vertebrates are space-filling cytoskeletal polymers called neurofilaments. Neurofilaments are also cargoes of axonal transport that move along microtubule tracks. Thus, neurofilaments define axonal morphology, but they are also in constant flux. The proposed research addresses this intriguing and physiologically important relationship. The central hypothesis is that the kinetics of neurofilament transport determines axonal neurofilament content, which in turn specifies axonal caliber and function. The specific goals are to determine the dynamic interplay between neurofilament transport velocity and flux in the specification of overall axon caliber, and how neurofilaments navigate local constrictions at the nodes of Ranvier. To accomplish these goals, the investigators will employ a tight integration of computational and mathematical methods with innovative live imaging of myelinated axons in peripheral nerves ex vivo from a new transgenic mouse that expresses a photoactivatable neurofilament protein in neurons.