Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation.
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.
Campbell
D S
DS
Department of Anatomy, University of Cambridge, Downing Street, CB2 3DY, Cambridge, United Kingdom.
Holt
C E
CE
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
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