As spindly, elongated cells, neurons must be able to transport proteins and receptors between distant sites in their cell bodies and axons to function properly. A new imaging study by researchers at Johns Hopkins University has now visualized the ebb and flow of the nerve growth factor receptor TrkA within neurons, via an unusual process known as transcytosis. Their study also explains how this phenomenon supports neuronal function and connectivity in mice.
Senior and corresponding author Rejji Kuruvilla, PhD, at Johns Hopkins University Department of Biology, and colleagues reported on their findings in Science Signaling, in a paper titled “Transcytosis-mediated anterograde transport of the receptor TrkA mediates the formation of presynaptic sites in sympathetic neurons.” In their paper, the authors concluded, “These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice … Our study suggests that transcytosis might be a more general mechanism than now appreciated for the targeted transport of trophic and guidance receptors, adhesion and synaptic proteins, as well as ion channels.”
The axons of neurons are extremely long compared to their main cell bodies, with axon terminals sometimes residing a long distance from the cell nucleus. “Axon terminals can be meters away from cell bodies where many axonal membrane proteins with critical functions in regulating axon guidance and growth, neuronal survival, presynaptic organization, and synaptic transmission are made,” the authors wrote.
Neurons need to be able to transport these proteins efficiently across these relatively vast distances. They do this by either directly sending the protein through a secretory pathway or via an indirect mechanism called transcytosis. The latter occurs when the central cell body takes in newly synthesized proteins or surface receptors, after which they move to axons through the cell cytoplasm. “Transcytosis is an atypical endocytosis-based mechanism, where newly synthesized proteins are first inserted on cell body surfaces, internalized, and anterogradely transported to axons,” the team continued.
Transcytosis is still relatively obscure and enigmatic compared with the direct secretion method, and questions remain about how exactly it sustains the function and connectivity of neurons. “In contrast to the considerable progress made in understanding the direct secretory pathway, there is limited knowledge about transcytosis, specifically the underlying transport kinetics and organelles involved, whether it occurs in vivo, and its contributions to neuronal connectivity and function,” the investigators noted.
Seeking answers, first author Kuruvilla, together with first author Guillermo Moya-Alvarado, PhD, and colleagues, used live cell imaging and electron microscopy to peer at the movement of receptors across compartments within mouse neurons.
They visualized the trafficking dynamics and transcytosis of a receptor named TrkA. “The family of tropomyosin-related kinase (Trk) receptors provides a prominent example of membrane proteins that undergo long-distance axonal trafficking to control neuronal survival, axon growth, and synaptic transmission,” the scientists explained.
Through their study, the authors noted various shifts in speed and direction as vesicles carried TrkA from the soma to axons. Using labeled TrkA proteins, the scientists also confirmed that transcytosis occurred within nerve terminals of living mice. “Live imaging and electron microscopy of compartmentalized cultures revealed that soma surface–derived TrkA proteins underwent dynamic transport within axons, with changes in speed, direction, and the vesicular organelles that carried them as they moved from proximal to distal axon compartments,” they stated. “In mice, soma surface–labeled TrkA proteins were observed in sympathetic nerve terminals, demonstrating that transcytosis occurs in vivo.”
![Assessing TrkA receptors transcytosis from cell bodies to nerve terminals in vivo. Superior cervical ganglion (SCG) in Ntrk1Flag mice, at postnatal day 2 to day 3 were injected in one of each paired ganglia per animal with the contralateral ganglion and target tissues (noninjected side) serving as internal controls to assess any systemic leakage of injected label. Representative image of the injected side. Flag (green) and sympathetic neurons (Tuj1, red) immunofluorescence in the superior cervical ganglia. DAPI is shown in blue. Scale bars, 50 μm. [All images and movies were generated by Guillermo Moya Alvarado]](https://www.genengnews.com/wp-content/uploads/2026/05/Low-Res_Fig-4H-002-300x300.jpg)
They also found that disrupting its transcytosis by introducing a point mutation into TrkA reduced the number and size of presynaptic sites and decreased synaptic transmission in culture and in rodents in vivo, confirming the importance of the process for neuronal physiology. “These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice,” the team concluded “Uncovering mechanisms of axon delivery has implications that extend beyond the healthy nervous system to understanding cell biological pathways that contribute to nerve repair after injury or neurodegeneration, because the correct complement of membrane proteins must be accurately targeted to regenerating axons to ensure functional recovery.”
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