Neurotrophins redirect p75NTR from a clathrin-independent to a clathrin-dependent endocytic pathway coupled to axonal transport

The p75 neurotrophin receptor (p75(NTR)) plays multiple roles in neuronal physiology through interactions with many ligands and coreceptors. However, its intracellular neuronal trafficking prior to and after neurotrophin activation is still poorly characterized. We have previously shown that in response to nerve growth factor (NGF), p75(NTR) is retrogradely transported along the axons of motor neurons (MNs) in carriers shared with NGF, brain-derived neurotrophic factor and the tyrosine kinase receptor TrkB. Here, we report that NGF does not enhance the internalization or degradation of p75(NTR), which undergoes a rapid dynamin-dependent and clathrin-independent recycling process in MNs. Instead, incubation of cells with NGF leads to the redirection of a pool of plasma membrane p75(NTR) into clathrin-coated pits. The subsequent internalization of p75(NTR) via clathrin-mediated endocytosis, as well as the activity of Rab5, are essential for the sorting of the p75(NTR)-containing endosomes to the axonal retrograde transport pathway and for the delivery of p75(NTR) to the soma. Our findings suggest that the spatial regulation of p75(NTR) signalling is controlled by these ligand-driven routes of endocytosis.