Correlation between semaphorin3A-induced facilitation of axonal transport and local activation of a translation initiation factor eukaryotic translation initiation factor 4E.
An impressive body of evidence has been accumulated indicating that local protein synthesis is implicated in navigation of neurite extension induced by guidance cues, such as semaphorin3A (Sema3A). We found previously that a Src type tyrosine kinase Fyn and cyclin-dependent kinase 5 (Cdk5) mediate Sema3A-signaling. We also showed that Sema3A elicits axonal transport through neuropilin-1, a receptor for Sema3A, located at the growth cones. Here, we investigate the relationship between Sema3A-induced local signaling, protein synthesis, and axonal transport. Lavendustin A, a tyrosine kinase inhibitor, and olomoucine, a cyclin-dependent kinase inhibitor, suppressed Sema3A-induced facilitation of anterograde and retrograde axonal transport in dorsal root ganglion (DRG) neuron with and without the cell body. Sema3A-induced facilitation of axonal transport was attenuated in DRG neurons of fyn- (fyn-/-) and a Cdk5 activator, p35 (p35-/-)-deficient mice when compared with those of wild-type or heterozygous mice. Inhibition of protein synthesis suppressed Sema3A-induced facilitation of axonal transport in the DRG neuron with and without the cell body. Sema3A enhanced the level of immunoreactivity of phosphorylated eukaryotic translation initiation factor 4E (eIF-4E) within 5 min in growth cones in a time course similar to that of the facilitated axonal transport. This enhanced signal for phospho-eIF4E was blocked by lavendustin A or olomoucine and was not detected in the fyn-/- and p35-/- neurons. These results provide evidence for a mutual regulatory mechanism between local protein synthesis and axonal transport.
Li
Chanxia
C
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Sasaki
Yukio
Y
Takei
Kohtaro
K
Yamamoto
Hiroshi
H
Shouji
Masayuki
M
Sugiyama
Yoshinobu
Y
Kawakami
Tadashi
T
Nakamura
Fumio
F
Yagi
Takeshi
T
Ohshima
Toshio
T
Goshima
Yoshio
Y
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007701:Kinetin; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011687:Purines / Q000494:pharmacology; D040121:Semaphorin-3A / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D009419:Nerve Tissue Proteins; D010636:Phenols; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D011687:Purines; D040121:Semaphorin-3A; C089495:neuronal Cdk5 activator (p25-p35); C062898:lavendustin A; C090046:olomoucine; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D007701:Kinetin