Differing semaphorin 3A concentrations trigger distinct signaling mechanisms in growth cone collapse.
Semaphorin-3A (Sema3A) is a major guidance cue in the developing nervous system. Previous studies have revealed a dependence of responses to Sema3A on local protein synthesis (PS) in axonal growth cones, but a recent study has called this dependence into question. To understand the basis of this discrepancy we used the growth cone collapse assay on chick dorsal root ganglion neurons. We show that the dependence of growth cone collapse on protein synthesis varies according to Sema3A concentration, from near-total at low concentration (<100 ng/ml) to minimal at high concentration (>625 ng/ml). Further, we show that neuropilin-1 (NP-1) mediates both PS-dependent and PS-independent collapse. Our findings are consistent with the operation of at least two distinct Sema3A signaling pathways: one that is PS-dependent, involving mammalian target of rapamycin, and one that is PS-independent, involving GSK-3β activation and operative at all concentrations of Sema3A examined. The results provide a plausible explanation for the discrepancy in PS-dependence reported in the literature, and indicate that different signaling pathways activated within growth cones can be modulated by changing the concentration of the same guidance cue.
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
Richard P C
RP
Manns
Geoffrey M W
GM
Cook
Christine E
CE
Holt
Roger J
RJ
Keynes
D000818:Animals; D001369:Axons / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D020439:Growth Cones / Q000187:drug effects*; D020932:Nerve Growth Factor / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D040121:Semaphorin-3A / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D011500:Protein Synthesis Inhibitors; D040121:Semaphorin-3A; D039942:Neuropilin-1; D020932:Nerve Growth Factor; D003513:Cycloheximide; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3