Arf6 mediates Schwann cell differentiation and myelination.
During development of the peripheral nervous system (PNS), Schwann cells wrap neuronal axons, becoming the myelin sheaths that help axonal functions. While the intercellular signals controlling the myelination process between Schwann cells and peripheral neurons are well studied, the transduction of these signals in Schwann cells still remains elusive. Here, we show that Arf6, an Arf protein of the small GTPase family, is involved in promoting the myelination process. Knockdown of Arf6 with the small-interfering (si)RNA in primary Schwann cells markedly decreases dibutyl-cyclic AMP-induced myelin marker protein expression, indicating that Arf6 plays a role in differentiation-like phenotypic changes. To obtain in vivo evidence, we generated small-hairpin (sh)RNA transgenic mice targeting Arf6 for Schwann cells. Transgenic mice exhibited reduced myelin thickness compared to littermate controls, consistent with the defective myelin formation observed in the transgenic mouse-derived Schwann cell and neuronal culture system. Transgenic mice also exhibited decreased phosphorylation of myelination-related signaling molecules such as Akt kinase cascade proteins as well as downregulation of myelin marker proteins. These results suggest that signaling through Arf6 is required for Schwann cell myelination, adding Arf6 to the list of intracellular signaling molecules involved in the myelination process.
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Tomohiro
T
Torii
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Yuki
Y
Miyamoto
Tsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan.
Masahiro
M
Yamamoto
Tsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan.
Katsuya
K
Ohbuchi
Department of Animal Facility, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Hideki
H
Tsumura
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Kazuko
K
Kawahara
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Akito
A
Tanoue
Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
Hiroyuki
H
Sakagami
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.
Junji
J
Yamauchi
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat
Arf6; Myelination; Nerve; Schwann cell; Signaling