title: Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation.
abstract: Growth cones contain mRNAs, translation machinery, and, as we report here, protein degradation machinery. We show that isolated retinal growth cones immediately lose their ability to turn in a chemotropic gradient of netrin-1 or Sema3A when translation is inhibited. Translation inhibition also prevents Sema3A-induced collapse, while LPA-induced collapse is not affected. Inhibition of proteasome function blocks responses to netrin-1 and LPA but does not affect Sema3A responses. We further demonstrate in isolated growth cones that netrin-1 and Sema3A activate translation initiation factors and stimulate a marked rise in protein synthesis within minutes, while netrin-1 and LPA elicit similar rises in ubiquitin-protein conjugates. These results suggest that guidance molecules steer axon growth by triggering rapid local changes in protein levels in growth cones.
authors.affiliation: Department of Anatomy, University of Cambridge, Downing Street, CB2 3DY, Cambridge, United Kingdom.
authors.forename: D S
authors.initials: DS
authors.lastname: Campbell
authors.forename: C E
authors.initials: CE
authors.lastname: Holt
mesh_terms: D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D020439:Growth Cones / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D000075388:Netrin-1; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000254:growth & development; D040121:Semaphorin-3A; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D014981:Xenopus
chemical_list: D000546:Amanitins; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D005136:Eye Proteins; D006023:Glycoproteins; D007976:Leupeptins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D009414:Nerve Growth Factors; D019384:Nucleic Acid Synthesis Inhibitors; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D040121:Semaphorin-3A; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C063261:acetylleucyl-leucyl-norleucinal; D000075388:Netrin-1; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; C080148:tor protein, Drosophila; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex