Summary 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 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 “gate-keeper” 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.

Neurons are morphologically characterized by long processes extending from a cell body. These processes, the dendrites and axon, are major sub-cellular compartments defined by morphological, molecular, and functional differences. However, evidence from vertebrates and invertebrates suggests that, based on molecular distribution, individual axons and dendrites are further divided into distinct compartments; many membrane molecules involved in axon guidance and synapse formation are localized to specific segments of axons or dendrites that share a boundary of localization. In this review, we describe recent progress in understanding the mechanisms of intra-neurite patterning, and discuss its potential roles in the development and function of the nervous system. Each protein employs different ways to achieve compartment-specific localization; some membrane molecules localize via cell-autonomous ability of neurons, while others require extrinsic signals for localization. The underlying regulatory mechanisms include transcriptional regulation, local translation, diffusion barrier, endocytosis, and selective membrane targeting. We propose that intra-neurite compartmentalization could provide platforms for structural and functional diversification of individual neurons.