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

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.

Keywords: ER; PTP1B; TrkA signaling endosomes; axon transport; neurotrophins; protein tyrosine phosphatase; sympathetic neuron development; transcytosis.