title: Phosphorylation of cytohesin-1 by Fyn is required for initiation of myelination and the extent of myelination during development.
abstract: Schwann cells respond to cues from axons by transforming their cellular morphology and forming myelin. We demonstrated that the guanine nucleotide exchange factor (GEF) cytohesin-1 promoted myelination by activating the small guanosine triphosphatase (GTPase) Arf6. In mice, ablating cytohesin-1 delayed myelination and diminished the amount of myelin produced. We determined that the Src-family kinase Fyn phosphorylated tyrosine 382 (Y(382)) of cytohesin-1, and we generated transgenic mice that expressed a Schwann cell-specific phosphorylation mutant of cytohesin-1 (Y382F) that could not be targeted by Fyn. During development, these transgenic mice displayed delayed myelination compared to that of wild-type mice, as well as a decrease in the amount of myelin produced, similar to that observed in cytohesin-1⁻/⁻ mice. These findings demonstrate that phosphorylation of cytohesin-1 by Fyn is required for full myelination and suggest that tyrosine phosphorylation of GEFs may be a mechanism to activate small GTPases engaged in cell morphogenesis.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Torii
authors.forename: Shou
authors.initials: S
authors.lastname: Takashima
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kondo
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Kawahara
authors.forename: Noriko
authors.initials: N
authors.lastname: Nemoto
authors.forename: Jonah R
authors.initials: JR
authors.lastname: Chan
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D009186:Myelin Sheath / Q000502:physiology*; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000502:physiology*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; C100723:cytohesin-1; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat