During the development of the nervous system, axons are directed to their cognate synaptic targets by guidance factors that exert either a repulsive or an attractive effect onto axons and growth cones. Disturbances in the intricately regulated process of axonal pathfinding interfere with the establishment of correct synaptic connections and the formation of proper neuronal circuitry. Consequently, alterations of axonal pathfinding are thought to cause a wide variety of neurodevelopmental disorders. Netrin-1 and NGF are attractive guidance cues that induce faster growth rates in axons, as well as growth cone elaboration and attractive turning. These morphological changes are mediated by the rearrangement of the highly dynamic actin and microtubules cytoskeleton within growth cones, and a great amount of prior research has addressed the intra-axonal signaling pathways governing these cytoskeletal changes. However, besides cytoskeletal growth the process of axon elongation and growth cone elaboration requires the rapid, massive enlargement of the cell surface. The phospholipids that make up the nascent plasma membrane are anterogradely transported along the axons from the cell bodies in the form of plasma membrane precursor vesicles (PPVs). These PPVs fuse with the growth cone membrane thereby enlarging the surface of axons and growth cones in a regulated process called polarized exocytosis. Plasma membrane expansion and cytoskeletal dynamics have to occur at the same site and at the same time to achieve axon outgrowth or turning. Currently, it is unknown how this synchronicity between two seemingly separate pathways is established. The goal of this application is to understand how these two molecular pathways, cytoskeletal rearrangement and polarized exocytosis of PPVs, are integrated and co-regulated downstream of netrin-1 and NGF signaling to result in the characteristic axonal outgrowth and growth cone turning that characterize the morphological response of axons to attractive guidance cues. Based on preliminary studies, a special focus of this research proposal is to understand the functional significance of intra-axonal mRNA translation for the co-activation of both pathways. The successful completion of this research will provide a coherent view of the signaling cascades that ensure the temporal-spatial concurrence of cytoskeletal dynamics and membrane expansion within distal axons and growth cones stimulated with attractive guidance cues.
During development, guidance molecules in the immature brain direct axons to their targets; disturbances in this process change neuronal connectivity and may underlie neurodevelopmental disorders. This research proposal is designed to elucidate the intra-axonal mechanisms governing axon outgrowth and will have broad relevance for the understanding of the etiology of mental health disorders.
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