Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors

Gregorio Valdez, Wendy Akmentin, Polyxeni Philippidou, Rejji Kuruvilla, David D. Ginty, Simon Halegoua

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5236-5247
Number of pages12
JournalJournal of Neuroscience
Volume25
Issue number21
DOIs
StatePublished - May 25 2005

Fingerprint

Nerve Growth Factor Receptors
Neurons
Nerve Growth Factors
Carisoprodol
Mitogen-Activated Protein Kinase 7
Multivesicular Bodies
Clathrin
Immunoelectron Microscopy
Endosomes
Brain-Derived Neurotrophic Factor
Receptor Protein-Tyrosine Kinases
Nerve Growth Factor
Dendrites
Fluorescence Microscopy
Confocal Microscopy
Axons
Membrane Proteins
Cell Membrane
Phenotype

Keywords

  • Apoptosis
  • Axon
  • Clathrin independent
  • Endocytosis
  • ERK
  • Nerve growth factor (NGF)
  • Neurite
  • Neurotrophin
  • Pheochromocytoma (PC12)
  • Signal transduction
  • Trafficking
  • Trophic

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Valdez, G., Akmentin, W., Philippidou, P., Kuruvilla, R., Ginty, D. D., & Halegoua, S. (2005). Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. Journal of Neuroscience, 25(21), 5236-5247. https://doi.org/10.1523/JNEUROSCI.5104-04.2005

Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. / Valdez, Gregorio; Akmentin, Wendy; Philippidou, Polyxeni; Kuruvilla, Rejji; Ginty, David D.; Halegoua, Simon.

In: Journal of Neuroscience, Vol. 25, No. 21, 25.05.2005, p. 5236-5247.

Research output: Contribution to journalArticle

Valdez, G, Akmentin, W, Philippidou, P, Kuruvilla, R, Ginty, DD & Halegoua, S 2005, 'Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors', Journal of Neuroscience, vol. 25, no. 21, pp. 5236-5247. https://doi.org/10.1523/JNEUROSCI.5104-04.2005
Valdez G, Akmentin W, Philippidou P, Kuruvilla R, Ginty DD, Halegoua S. Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. Journal of Neuroscience. 2005 May 25;25(21):5236-5247. https://doi.org/10.1523/JNEUROSCI.5104-04.2005
Valdez, Gregorio ; Akmentin, Wendy ; Philippidou, Polyxeni ; Kuruvilla, Rejji ; Ginty, David D. ; Halegoua, Simon. / Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 21. pp. 5236-5247.
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