The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally and molecularly defined multivesicular bodies (MVBs). In contrast to MVBs that carry non-TrkA cargoes from distal axons to cell bodies, retrogradely transported TrkA+ MVBs that arrive in cell bodies evade lysosomal fusion and instead evolve into TrkA+ single-membrane vesicles that are signaling competent. Moreover, TrkA kinase activity associated with retrogradely transported TrkA+ MVBs determines TrkA+ endosome evolution and fate. Thus, MVBs deliver long-range retrograde NGF signals and serve as signaling and sorting platforms in the cell soma, and MVB cargoes dictate their vesicular fate.

Summary Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies also translocate into dendrites, where they are signaling-competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially-confined inhibition of TrkA kinase activity, we found that distal axon-derived TrkA signaling endosomes are necessary specifically within sympathetic neuron dendrites for maintenance of synapses. Thus, TrkA signaling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome signaling within dendrites to promote aggregation of postsynaptic protein complexes.