title: Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival.
abstract: The neurotrophins NGF and NT3 collaborate to support development of sympathetic neurons. Although both promote axonal extension via the TrkA receptor, only NGF activates retrograde transport of TrkA endosomes to support neuronal survival. Here, we report that actin depolymerization is essential for initiation of NGF/TrkA endosome trafficking and that a Rac1-cofilin signaling module associated with TrkA early endosomes supports their maturation to retrograde transport-competent endosomes. These actin-regulatory endosomal components are absent from NT3/TrkA endosomes, explaining the failure of NT3 to support retrograde TrkA transport and survival. The inability of NT3 to activate Rac1-GTP-cofilin signaling is likely due to the labile nature of NT3/TrkA complexes within the acidic environment of TrkA early endosomes. Thus, TrkA endosomes associate with actin-modulatory proteins to promote F-actin disassembly, enabling their maturation into transport-competent signaling endosomes. Differential control of this process explains how NGF but not NT3 supports retrograde survival of sympathetic neurons.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Harrington
authors.forename: Coryse
authors.initials: C
authors.lastname: St Hillaire
authors.forename: Larry S
authors.initials: LS
authors.lastname: Zweifel
authors.forename: Natalia O
authors.initials: NO
authors.lastname: Glebova
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Philippidou
authors.forename: Simon
authors.initials: S
authors.lastname: Halegoua
authors.forename: David D
authors.initials: DD
authors.lastname: Ginty
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism; D016716:PC12 Cells; D021381:Protein Transport; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000166:cytology
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D020933:Neurotrophin 3; D020932:Nerve Growth Factor; D020917:Receptor, trkA