Axonal Targeting of Trk Receptors via Transcytosis Regulates Sensitivity to Neurotrophin Responses

Axonal targeting of trophic receptors is critical for neuronal responses to extracellular developmental cues, yet the underlying trafficking mechanisms remain unclear. Here, we report that tropomyosin-related kinase (Trk) receptors for target-derived neurotrophins are anterogradely trafficked to axo...

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Bibliographic Details
Published in:The Journal of neuroscience 2009-09, Vol.29 (37), p.11674-11685
Main Authors: Ascano, Maria, Richmond, Alissa, Borden, Philip, Kuruvilla, Rejji
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Animals, Newborn
Axons - drug effects
Axons - metabolism
Axons - physiology
Biotinylation - methods
Cell Survival - drug effects
Cells, Cultured
Dynamins - metabolism
Endocytosis - drug effects
Exocytosis - drug effects
Green Fluorescent Proteins - genetics
Immunoprecipitation
Microscopy, Confocal
Nerve Growth Factor - pharmacology
Neurons - cytology
Neurons - drug effects
Neurons - physiology
Protein Transport - drug effects
rab GTP-Binding Proteins - metabolism
Rats
Rats, Sprague-Dawley
Receptor, trkA - genetics
Receptor, trkA - metabolism
Signal Transduction - drug effects
Signal Transduction - physiology
Superior Cervical Ganglion - cytology
Time Factors
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Summary:Axonal targeting of trophic receptors is critical for neuronal responses to extracellular developmental cues, yet the underlying trafficking mechanisms remain unclear. Here, we report that tropomyosin-related kinase (Trk) receptors for target-derived neurotrophins are anterogradely trafficked to axons via transcytosis in sympathetic neurons. Using compartmentalized cultures, we show that mature receptors on neuronal soma surfaces are endocytosed and remobilized via Rab11-positive recycling endosomes into axons. Inhibition of dynamin-dependent endocytosis disrupted anterograde transport and localization of TrkA receptors in axons. Anterograde TrkA delivery and exocytosis into axon growth cones is enhanced by nerve growth factor (NGF), acting locally on distal axons. Perturbing endocytic recycling attenuated NGF-dependent signaling and axon growth while enhancing recycling conferred increased neuronal sensitivity to NGF. Our results reveal regulated transcytosis as an unexpected mode of Trk trafficking that serves to rapidly mobilize ready-synthesized receptors to growth cones, thus providing a positive feedback mechanism by which limiting concentrations of target-derived neurotrophins enhance neuronal sensitivity.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1542-09.2009