Transcytosis-mediated anterograde transport of TrkA receptors is necessary for sympathetic neuron development and function

Blaine Connor, Guillermo Moya-Alvarado, Naoya Yamashita, Rejji Kuruvilla

Research output: Contribution to journalArticlepeer-review

Abstract

In neurons, many membrane proteins, synthesized in cell bodies, must be efficiently delivered to axons to influence neuronal connectivity, synaptic communication, and repair. Previously, we found that axonal targeting of TrkA neurotrophin receptors in sympathetic neurons occurs via an atypical transport mechanism called transcytosis, which relies on TrkA interactions with PTP1B, a protein tyrosine phosphatase. Here, we generated TrkAR685A mice, where TrkA receptor signaling is preserved, but its PTP1B-dependent transcytosis is disrupted to show that this mode of axonal transport is essential for sympathetic neuron development and autonomic function. TrkAR685A mice have decreased axonal TrkA levels in vivo, loss of sympathetic neurons, and reduced innervation of targets. The neuron loss and diminished target innervation phenotypes are specifically restricted to the developmental period when sympathetic neurons are known to rely on the TrkA ligand, nerve growth factor, for trophic support. Postnatal TrkAR685A mice exhibit reduced pupil size and eyelid ptosis, indicative of sympathetic dysfunction. Furthermore, we also observed a significant loss of TrkA-expressing nociceptive neurons in the dorsal root ganglia during development in TrkAR685A mice, suggesting that transcytosis might be a general mechanism for axonal targeting of TrkA receptors. Together, these findings establish the necessity of transcytosis in supplying TrkA receptors to axons, specifically during development, and highlight the physiological relevance of this axon targeting mechanism in the nervous system.

Original languageEnglish (US)
Pages (from-to)e2205426120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number6
DOIs
StatePublished - Feb 7 2023

Keywords

  • PTP1B tyrosine phosphatase
  • TrkA receptors
  • axon transport
  • sympathetic neuron development
  • transcytosis

ASJC Scopus subject areas

  • General

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