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The Journal of Neuroscience, May 25, 2005, 25(21):5236-5247; doi:10.1523/JNEUROSCI.5104-04.2005

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Development/Plasticity/Repair
Pincher-Mediated Macroendocytosis Underlies Retrograde Signaling by Neurotrophin Receptors

Gregorio Valdez,¹ Wendy Akmentin,¹ Polyxeni Philippidou,¹ Rejji Kuruvilla,² David D. Ginty,² and Simon Halegoua¹

¹Department of Neurobiology and Behavior, Center for Brain and Spinal Cord Research, State University of New York at Stony Brook, Stony Brook, New York 11794-5230, and ²Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Retrograde signaling by neurotrophins is crucial for regulating neuronal phenotype and survival. The mechanism responsible for retrograde signaling has been elusive, because the molecular entities that propagate Trk receptor tyrosine kinase signals from the nerve terminal to the soma have not been defined. Here, we show that the membrane trafficking protein Pincher defines the primary pathway responsible for neurotrophin retrograde signaling in neurons. By both immunofluorescence confocal and immunoelectron microscopy, we find that Pincher mediates the formation of newly identified clathrin-independent macroendosomes for Trk receptors in soma, axons, and dendrites. Trk macroendosomes are derived from plasma membrane ruffles and subsequently processed to multivesicular bodies. Pincher similarly mediates macroendocytosis for NGF (TrkA) and BDNF (TrkB) in both peripheral (sympathetic) and central (hippocampal) neurons. A unique feature of Pincher-Trk endosomes is refractoriness to lysosomal degradation, which ensures persistent signaling through a critical effector of retrograde survival signaling, Erk5 (extracellular signal-regulated kinase 5). Using sympathetic neurons grown in chamber cultures, we find that block of Pincher function, which prevents Trk macroendosome formation, eliminates retrogradely signaled neuronal survival. Pincher is the first distinguishing molecular component of a novel mechanistic pathway for endosomal signaling in neurons.

Key words: apoptosis; axon; neurite; nerve growth factor (NGF); pheochromocytoma (PC12); trophic; trafficking; ERK; signal transduction; neurotrophin; endocytosis; clathrin independent

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Received Dec 14, 2004; revised April 19, 2005; accepted April 21, 2005.

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