| The mammalian nervous system is comprised of billions of neurons, forming intricate neural networks, dedicated to processing and relaying a multitude of information. How these networks are formed, refined, and maintained is a fundamental question of neurobiology. It has long been established that the targets of developing neurons play an integral role in the formation of neuronal connections, through a vast array of secreted and membrane bound cues. Of these cues, the neurotrophins are perhaps the best described, initiating developmental programs required for process growth, target innervation, cell death, and synaptogenesis. Central to neurotrophin function is their ability to modulate these developmental programs by communicating information over long-distances, from the furthest reaches of the axon to the remote neuronal cell body, yet the mechanisms by which these trophic factors signal retrogradely and how they coordinate these developmental processes remain largely unknown. We have investigated the roles of neuronal targets, intermediate and final, and the neurotrophins derived from them, for axon growth, target innervation, and cell survival. In addition, we have investigated the mechanisms by which these target-derived factors signal to mediate their distinctive functions during development. We observed a unique signal transduction cascade for the development of sympathetic neurons, in which two target-derived neurotrophic factors, NT-3 and NGF, activate the same neurotrophin receptor, TrkA, to coordinate the growth and survival of these neurons. We also established and optimized multiple steps towards the purification of the signaling endosome, the elusive carrier of the retrograde neurotrophin signal. |
