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

Abstract

The p75 neurotrophin receptor (p75NTR) 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), p75NTR 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 p75NTR, 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 p75NTR into clathrin-coated pits. The subsequent internalization of p75NTR via clathrin-mediated endocytosis, as well as the activity of Rab5, are essential for the sorting of the p75NTR-containing endosomes to the axonal retrograde transport pathway and for the delivery of p75NTR to the soma. Our findings suggest that the spatial regulation of p75NTR signalling is controlled by these ligand-driven routes of endocytosis. © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd.