Transcytosis-mediated anterograde transport of the receptor TrkA mediates the formation of presynaptic sites in sympathetic neurons

In neurons, many membrane proteins that are synthesized in the cell body must be efficiently delivered to axons to regulate neuronal connectivity. Transcytosis is an atypical transport mode in which membrane proteins internalized from soma membranes are transported to axons in an anterograde fashion. Here, we characterized the trafficking dynamics and mechanism of transcytosis of the receptor TrkA from the soma in response to nerve growth factor (NFG) signaling at the axon in mouse sympathetic neurons. Live imaging and electron microscopy of compartmentalized cultures revealed that soma surface-derived TrkA proteins underwent dynamic transport in axons, with changes in speed, direction, and the vesicular organelles that carried them as they moved from proximal to distal axon compartments. In mice, soma surface-labeled TrkA proteins were observed in sympathetic nerve terminals, demonstrating that transcytosis occurs in vivo. Transcytosed TrkA proteins were enriched at presynaptic varicosities, bouton-like structures that store and release neurotransmitters. Disrupting its transcytosis by introducing a point mutation into TrkA reduced the number and size of presynaptic sites and decreased synaptic transmission in vivo and in culture. These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice.