Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling.
Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A-specific fragment NogoDelta20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that NogoDelta20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of NogoDelta20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoDelta20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program.
Joset
Armela
A
Brain Research Institute, University of Zurich, Zurich, Switzerland. hatkic@hifo.uzh.ch
Dodd
Dana A
DA
Halegoua
Simon
S
Schwab
Martin E
ME
D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005727:Ganglia, Spinal / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D000070798:Nogo Proteins; D009924:Organ Culture Techniques; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
C456611:Ehd4 protein, rat; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat; D000242:Cyclic AMP; D020742:rhoA GTP-Binding Protein