Target-derived nerve growth factor (NGF), by activating its receptor TrkA on distal axons, supports survival, growth and maintenance of connectivity of postganglionic sympathetic neurons and small-diameter primary sensory neurons of the peripheral nervous system (PNS). Long-range retrograde NGF signals are propagated by TrkA+ signaling endosomes, yet signaling endosome properties and their mechanisms of formation, axonal trafficking and signaling are poorly understood. The prevailing view is that Rab5+ early endosomes mediate retrograde NGF signals. In this study, we showed that ultrastructurally- and molecularly-defined multi-vesicular bodies (MVBs), but not early endosomes, are major carriers of retrograde NGF signals. Importantly, retrogradely transported TrkA+ MVBs in cell bodies associate with key effectors of TrkA, suggesting that they are bona fide signaling endosomes. Moreover, we found that, Rab7, a key regulator of MVB function, mediates survival and synaptogenesis of sympathetic neurons in vivo. Rab7 and its effector protein RILP, are associated with TrkA MVBs and are required for retrograde TrkA transport and survival in vitro. Remarkably, in contrast to MVBs carrying a variety of non-TrkA cargoes, retrogradely transported TrkA+ MVBs that arrive in cell bodies evolve into TrkA+ single-membrane vesicles (SVs) that evade lysosomal fusion. This novel population of TrkA SVs are signaling competent and therefore can contribute to NGF signal transduction. Molecularly, TrkA SVs are not Rab5+. Instead, a significant portion of TrkA SVs are associated with Vps35, a key component of the retromer complex. Lastly, TrkA kinase activity associated with retrogradely transported TrkA+ MVBs critically determines TrkA+ endosome evolution and fate. Thus, MVBs uniquely mediate long-range axonal transport of TrkA and serve as essential signaling and sorting platforms in the cell soma, and MVB cargoes dictate their vesicular fate.
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