Abstract
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.
Highlights
Developing neurons in the peripheral nervous system (PNS) are critically dependent on targetderived trophic cues released by the end organs they innervate
While application of neither the primary antibody nor Protein A-5nm gold alone to distal axons of compartmentalized Ntrk1Flag neurons yielded electron-dense structures detectable by electron microscopy (EM), application of anti-Flag antibody that was pre-conjugated to Protein A-5nm gold to Ntrk1Flag neurons, but not wild-type neurons, labeled electron dense structures in axons that were readily apparent by EM (Figure 1A)
Following nerve growth factor (NGF) treatment of distal axons, newly internalized TrkA in distal axons is associated with early endosomes, whereas following retrograde transport to proximal axons and cell bodies TrkA is predominantly associated with multivesicular bodies (MVBs)
Summary
Developing neurons in the peripheral nervous system (PNS) are critically dependent on targetderived trophic cues released by the end organs they innervate. A remarkable feature of NGF signaling is that, in order to elicit trophic actions on developing sensory and sympathetic neurons, the NGF/ TrkA signal must be propagated retrogradely, from distal axons to the soma, traveling a distance that is thousands of times the diameter of the cell body (Cosker et al, 2008; Howe and Mobley, 2005). A long-standing, canonical view is that retrograde NGF/TrkA signaling endosomes are early endosomes because, like other ligand/receptor complexes, internalized NGF/TrkA complexes are sorted into early endosomes and the membrane topology of receptors in early endosome-type vesicles can, in principle, enable signal propagation within the cytoplasm (Cosker et al, 2008; Harrington and Ginty, 2013; Howe and Mobley, 2005). MVBs are mediators of long-range retrograde TrkA signaling, evading lysosomal fusion and degradation within the soma in a TrkA kinase-dependent manner, and evolving within the soma into single membrane vesicles with the capacity to propagate TrkA survival signals
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