Nerve Growth Cone Locomotion

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Probably the most important part of the growing axon is the structure at its tip, the growth cone. Nerve growth cones are essential for directed axonal outgrowth. They are complex sensory-motor machines that respond to environmental cues through cell surface receptors or changes in ion channel permeability. They locally process this information using signal transduction pathways that regulate the motility mechanism responsible for driving forward advancement through the environment. Relatively little is known about the specific mechanisms that integrate the information and regulate its affect on motility. Although signal transduction pathways have been implicated, it has been difficult to link these pathways to specific effecter mechanisms of motility that persist over time. One effecter mechanism is the generation of force by myosin. Myosin activity has multiple roles that include the control of growth cone shape changes and the generation of traction force that drives forward advancement. It is an important effecter of growth cone motility that may be essential for changes in direction of advancement. My overall goal is to identify the various myosins responsible for modulating growth cone motility, understand how pathways that are stimulated by specific environmental cues control myosin activity and how the force that is developed is coupled to the extracellular environment to provide traction force. I propose that myosin II is the most important of the myosins identified in growth cones for regulating motility and producing traction force. I will test this proposal by eliminating the activity of myosin II and then measuring key aspects of motility including traction force. I also plan to identify the major pathways involved in growth cone myosin II regulation. Combined these results will provide the framework for understanding the molecular basis of growth cone motility and how environmental cues stimulate specific pathways to regulate this motility. This is essential for understanding the formation of neuronal circuitry during development and the mechanisms required for successful nerve regeneration.