title: Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac.
abstract: Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension is stimulated by the neurotrophin nerve growth factor (NGF), we found that the precursor of NGF, proNGF, induced acute collapse of growth cones of cultured hippocampal neurons. This retraction was initiated by an interaction between the p75 neurotrophin receptor (p75NTR) and the sortilin family member SorCS2 (sortilin-related VPS10 domain-containing receptor 2). Binding of proNGF to the p75NTR-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine nucleotide exchange factor Trio from the p75NTR-SorCS2 complex, resulting in decreased Rac activity and, consequently, growth cone collapse. The actin-bundling protein fascin was also inactivated, contributing to the destabilization and collapse of actin filaments. These results identify a bifunctional signaling mechanism by which proNGF regulates actin dynamics to acutely modulate neuronal morphology.
authors.affiliation: Department of Cell Biology, Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Deinhardt
authors.forename: Taeho
authors.initials: T
authors.lastname: Kim
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Spellman
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D020439:Growth Cones / Q000502:physiology* / Q000648:ultrastructure; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000502:physiology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020800:Receptor, Nerve Growth Factor; D011956:Receptors, Cell Surface; C020324:fascin; D020744:rac GTP-Binding Proteins