Formation of specific neuronal connections requires accurate guidance of developing axons to their correct targets by a variety of surface-bound and diffusible guidance cues. Axon guidance is also critically important for functional repair of damaged neuronal connections after brain injuries and diseases. During guidance, the motile growth cone at the tip of the axon senses direction from extracellular space and steers the axon through the complex environment of developing embryos to reach its specific target. Significant progress has been made in recent years towards the molecular identification of a variety of surface-bound and diffusible guidance molecules. However, the cellular mechanisms underlying directional sensing and steering of the growth cone remain largely unknown. The proposed study aims to understand how the growth cone responds to different types of diffusible guidance molecules to steer in a particular direction. The working hypothesis to be tested is as follow: different extracellular cues can act through different signaling pathways, but they all elicit localized signaling cascades that target the cytoskeleton in a spatially and temporally restricted fashion to cause the growth cone to steer in a specific direction. Taking advantage of the large size of Xenopus growth cones, an in vitro system for rigorous assay of growth cone turning, and a combination of high-resolution digital imaging and intracellular manipulation techniques, the research team plans to thoroughly investigate the cellular components associated with and, particularly, responsible for specific steering behaviors (attractive or repulsive) of the growth cone. The proposed project has four specific aims: (1) to determine the asymmetric motile activities associated with and/or responsible for growth cone attractive and repulsive turning, respectively, (2) to examine the local cytoskeletal events associated with attraction and repulsion respectively, (3) to elucidate the precise role of the microtubules and actin cytoskeleton, as well as their interactions, in steering the growth cone, and (4) to determine whether and how spatially- and temporally-regulated membrane recycling contributes to guided growth cone steering. The long-term goal is to identify the cellular events that are common as well as specific for attractive and repulsive turning, respectively, thus achieving a better understanding towards the cellular mechanisms underlying axon guidance for the generation of highly ordered brain architecture.
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