The role of TrkA positive extracellular vesicles in sympathetic neuron survival and maturation

University Of Virginia, Charlottesville VA

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Abstract

Vertebrate nervous systems contain billions of neurons and trillions of synapses but only thousands of genes. My research centers on how these limited number of genes can generate the diversity of connections required to build a functional nervous system. A central premise of this proposal is that single factors must act in multiple ways. For example the trophic factor NGF can act on multiple receptors at multiple subcellular locales to promote survival, death, synapse formation or axon branch stabilization. Here I seek to understand other mechanisms by which NGF can diversify its function to play multiple roles in nervous system formation. I expect that the findings here will be generalizable to multiple growth factors that govern nervous system development. One receptor that NGF binds to is a receptor tyrosine kinase, TrkA. Upon binding (typically at distal axons), this complex can signal locally to promote processes like axon growth and branching, or internalize into what is commonly referred to as the signaling endosome. I have become intensely interested in the fate and maturation of this endosome since it is likely that these events will relate to the functions that NGF-TrkA can influence. Beyond known effector conversions and trafficking events around the cell body and dendrite, I have found that these signaling endosomes can be packaged and secreted in what we call neurotrophic extracellular vesicles (EVs). Furthermore, these signaling EVs are capable classical neurotrophic functions in cultured sympathetic neurons: 1) the EVs protect against NGF-deprivation induced apoptosis, and 2) the EVs promote exuberant axon branching in cultured sympathetic neurons. To complement these preliminary data, I plan to fully characterize the biogenesis of these neurotrophic extracellular vesicles, including: 1) examination of what factors, such as neurotrophin exposure, neural activity, or starvation may influence EV production, 2) determine the source of TrkA enriched in the EVs, and 3) characterize the TrkA+ SE trafficking preceding EV production. Further, I will continue to 4) assess the neurotrophic function (cell survival/death and axon behavior) of TrkA+ EVs on sympathetic neurons. This proposal is designed to fill a gap in our knowledge with regard to neurotrophic extracellular vesicles that will lead to a more complete understanding of the formation of the peripheral nervous system.