title: Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves.
abstract: In postnatal development of the peripheral nervous system (PNS), Schwann cells differentiate to insulate neuronal axons with myelin sheaths, increasing the nerve conduction velocity. To produce the mature myelin sheath with its multiple layers, Schwann cells undergo dynamic morphological changes. While extracellular molecules such as growth factors and cell adhesion ligands are known to regulate the myelination process, the intracellular molecular mechanism underlying myelination remains unclear. In this study, we have produced Schwann cell-specific conditional knockout mice for cytohesin-2, a guanine-nucleotide exchange factor (GEF) specifically activating Arf6. Arf6, a member of the Ras-like protein family, participates in various cellular functions including cell morphological changes. Cytohesin-2 knockout mice exhibit decreased Arf6 activity and reduced myelin thickness in the sciatic nerves, with decreased expression levels of myelin protein zero (MPZ), the major myelin marker protein. These results are consistent with those of experiments in which Schwann cell-neuronal cultures were treated with pan-cytohesin inhibitor SecinH3. On the other hand, the numbers of Ki67-positive cells in knockout mice and controls are comparable, indicating that cytohesin-2 does not have a positive effect on cell numbers. Thus, signaling through cytohesin-2 is required for myelination by Schwann cells, and cytohesin-2 is added to the list of molecules known to underlie PNS myelination.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Torii
authors.affiliation: Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan; School of Life Science, The Graduate University for Advanced Studies and The National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Glycobiology Research Unit, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan.
authors.forename: Shou
authors.initials: S
authors.lastname: Takashima
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan. Electronic address: yamauchi-j@ncchd.go.jp.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D020690:GTPase-Activating Proteins; C102474:cytohesin-2
keywords: Arf6; Conditional knockout mouse; Cytohesin-2; Myelination; Schwann cell