Trafficking the NGF signal: implications for normal and degenerating neurons

Jean-Dominique Delcroix; Janice Valletta; Chenbiao Wu; Charles L Howe; Chun-Fai Lai; John D Cooper; Pavel V Belichenko; Ahmad Salehi; William C Mobley

doi:10.1016/s0079-6123(03)46001-9

Trafficking the NGF signal: implications for normal and degenerating neurons

Prog Brain Res. 2004:146:3-23. doi: 10.1016/s0079-6123(03)46001-9.

Authors

Jean-Dominique Delcroix¹, Janice Valletta, Chenbiao Wu, Charles L Howe, Chun-Fai Lai, John D Cooper, Pavel V Belichenko, Ahmad Salehi, William C Mobley

Affiliation

¹ Department of Neurology and Neurological Sciences and of Pediatrics, Program in Neuroscience, Stanford University, Stanford, CA 94305, USA.

PMID: 14699953
DOI: 10.1016/s0079-6123(03)46001-9

Abstract

Nerve growth factor (NGF) activates TrkA to trigger signaling events that promote the survival, differentiation and maintenance of neurons. The mechanism(s) that controls the retrograde transport of the NGF signal from axon terminals to neuron cell bodies is not known. The 'signaling endosome' hypothesis stipulates that NGF, TrkA and signaling proteins are retrogradely transported on endocytic vesicles. Here, we provide evidence for the existence of signaling endosomes. Following NGF treatment, clathrin-coated vesicles (CCVs) contain NGF bound to TrkA together with activated signaling proteins of the Ras/pErk1/2 pathway. NGF signals from isolated CCVs through the Erk1/2 pathway. Early endosomes appear to represent a second type of signaling endosomes. We found that NGF induced a sustained activation of Rap1, a small monomeric GTP-binding protein of the Ras family, and that this activation occurred in early endosomes that contain key elements of Rap1/pErk1/2 pathway. We discuss the possibility that the failure of retrograde NGF signaling in a mouse model of Down syndrome (Ts65Dn) may be due to the failure to retrograde transport signaling endosomes. It is important to define further the significance of signaling endosomes in the biology of both normal and degenerating neurons.

Publication types

Comparative Study

MeSH terms

Adaptor Protein Complex 2 / metabolism
Animals
Blotting, Western / methods
Brain / cytology
Brain / drug effects
Brain / metabolism
Cadaverine / analogs & derivatives*
Cadaverine / pharmacology
Calcium-Binding Proteins / metabolism
Carrier Proteins / metabolism
Chlorpromazine / pharmacology
Chromosomal Proteins, Non-Histone / metabolism
Coated Vesicles / drug effects
Coated Vesicles / metabolism
Cyclic AMP Response Element-Binding Protein / metabolism
Dopamine Antagonists / pharmacology
Endosomes / metabolism
Fluorescent Antibody Technique / methods
Membrane Proteins / metabolism
Mice
Mice, Transgenic
Microscopy, Electron
Nerve Degeneration / metabolism*
Nerve Growth Factor / metabolism
Nerve Growth Factor / physiology*
Neurons / drug effects
Neurons / metabolism*
PC12 Cells
Phosphotyrosine / metabolism
Potassium / pharmacology
Precipitin Tests / methods
Protein Transport / physiology*
Radioligand Assay
Rats
Receptor, trkA*
Signal Transduction / physiology*
Time Factors
Vesicular Transport Proteins
rap1 GTP-Binding Proteins / metabolism

Substances

Adaptor Protein Complex 2
Calcium-Binding Proteins
Carrier Proteins
Chromosomal Proteins, Non-Histone
Cyclic AMP Response Element-Binding Protein
Dopamine Antagonists
Membrane Proteins
Vesicular Transport Proteins
early endosome antigen 1
caltractin
Phosphotyrosine
Nerve Growth Factor
Receptor, trkA
rap1 GTP-Binding Proteins
monodansylcadaverine
Cadaverine
Potassium
Chlorpromazine