Target-derived NGF mediates axon growth and synapse assembly in sympathetic neurons via endocytic signaling mechanisms. (a) Retrograde NGF signaling, likely via axonal transport of TrkA-signaling endosomes, activates transcription factors and the expression of downstream target genes essential for long-term axon growth and target innervation. (b) Local NGF-TrkA signaling from an endocytic platform in axons promotes axon growth. NGF-TrkA complexes are endocytosed via a signaling pathway that includes Phospholipase C-γ, calcineurin and dynamin1. Internalization of TrkA in distal axons is required for short-term axon growth, in a manner independent of transcriptional responses. (c) NGF-TrkA signaling endosomes are retrogradely transported long-distance from axon terminals to the distal dendrites of sympathetic neurons. In dendrites, NGF-TrkA endosomal complexes signal via the MEK/MAPK pathway to regulate the clustering of acetylcholine receptors (nAChRs) and pre-existing postsynaptic density components including MAGUK, GKAP and Shank. Endosomal TrkA signaling modulates the assembly of postsynaptic components, in part, by restricting the anti-synaptic actions of p75 signaling in dendrites.

Axonal trafficking of survival and apoptotic signals underlie a developmental competition for target-derived NGF. In competing neurons, retrograde NGF signaling regulates a positive feedback loop by which NGF enhances sensitivity to itself by activating the transcription of its receptor, TrkA. Increased responsiveness to ligand may also result from anterograde transcytosis of TrkA receptors from soma surfaces to axon terminals via Rab11-positive recycling endosomes. In winning neurons, retrograde NGF signaling regulates the transcription of BDNF and NT-4 that then exert a paracrine effect on punishing/killing neighboring neurons that do not gain sufficient access to NGF. BDNF/NT-4-dependent apoptosis is mediated by p75 receptors expressed on the “losing” neurons. DLK, JNK and JIP3 may be part of an apoptotic complex that is activated locally in axons upon NGF deprivation and retrogradely transported to mediate c-jun phosphorylation in cell bodies and neuronal cell death. Developmental apoptosis may also be elicited by target-derived pro-neurotrophins, such as pro-NT-3, that act on axon terminals to initiate a retrograde death signal, likely via activation of a p75-sortilin receptor complex. It remains to be determined if similar or distinct retrograde signals are activated upon NGF deprivation and by pro-neurotrophins.