title: Signaling through Arf6 guanine-nucleotide exchange factor cytohesin-1 regulates migration in Schwann cells.
abstract: During development of the peripheral nervous system (PNS), Schwann cells migrate along neuronal axons before initiating myelination of the axons. While intercellular signals controlling migration, between Schwann cells and peripheral neurons, are established, how their intracellular transduction of the signals into Schwann cells still remains to be clarified. Here, we show that cytohesin-1, a guanine-nucleotide exchange factor (GEF), and the effector Arf6 are required for migration of primary Schwann cells. Knockdown of cytohesin-1 or Arf6 in Schwann cells, as well as treatment with the chemical cytohesin inhibitor SecinH3 or knockout of cytohesin-1, inhibits peripheral neuronal conditioned medium-mediated migration. Similar effects are also observed following stimulation with each of growth factors contained in a conditioned medium, suggesting that cytohesin-1 plays a role in transducing soluble ligand signals from neurons. Reintroduction of small interfering (si)RNA-resistant cytohesin-1 into Schwann cells reverses blunted migration in the siRNA-transfected Schwann cells, illustrating the importance of cytohesin-1 in migration. On the other hand, introduction of cytohesin-1 that harbors the Tyr-382 mutation, which is an amino acid that is important for its activation, failed to reverse the reduction in primary Schwann cell migration. These results suggest that signaling through cytohesin-1 is required for Schwann cell migration, revealing a novel mechanism for Schwann cell migration.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Torii
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shou
authors.initials: S
authors.lastname: Takashima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000089982:ADP-Ribosylation Factor 6; D017077:Culture Media, Conditioned; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; C516025:SecinH3; D014230:Triazoles; C100723:cytohesin-1; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat