Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors

Naoya Yamashita, Rajshri Joshi, Sheng Zhang, Zhong Yin Zhang, Rejji Kuruvilla

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Axonal targeting of signaling receptors is essential for neuronal responses to extracellular cues. Here, we report that retrograde signaling by target-derived nerve growth factor (NGF) is necessary for soma-to-axon transcytosis of TrkA receptors in sympathetic neurons, and we define the molecular underpinnings of this positive feedback regulation that enhances neuronal sensitivity to trophic factors. Activated TrkA receptors are retrogradely transported in signaling endosomes from distal axons to cell bodies, where they are inserted on soma surfaces and promote phosphorylation of resident naive receptors, resulting in their internalization. Endocytosed TrkA receptors are then dephosphorylated by PTP1B, an ER-resident protein tyrosine phosphatase, prior to axonal transport. PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a “gatekeeper” mechanism that ensures targeting of inactive receptors to axons to engage with ligand. In mice, PTP1B deletion reduces axonal TrkA levels and attenuates neuron survival and target innervation under limiting NGF (NGF+/−) conditions. Yamashita et al. describe a positive feedback mechanism in which retrogradely transported TrkA signaling endosomes control the anterograde transcytosis of naive somatic TrkA receptors to enhance receptor availability in sympathetic axons. Furthermore, an ER-resident protein tyrosine phosphatase acts specifically in neuronal soma to positively regulate TrkA axon targeting and trophic functions.

Original languageEnglish (US)
Pages (from-to)626-639.e5
JournalDevelopmental Cell
Volume42
Issue number6
DOIs
StatePublished - Sep 25 2017
Externally publishedYes

Keywords

  • ER
  • PTP1B
  • TrkA signaling endosomes
  • axon transport
  • neurotrophins
  • protein tyrosine phosphatase
  • sympathetic neuron development
  • transcytosis

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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