In Vivo Expression of the Arf6 Guanine-Nucleotide Exchange Factor Cytohesin-1 in Mice Exhibits Enhanced Myelin Thickness
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In Vivo Expression of the Arf6 Guanine-Nucleotide Exchange Factor Cytohesin-1 in Mice Exhibits Enhanced Myelin Thickness in Nerves Tomohiro Torii & Yuki Miyamoto & Naoko Onami & Hideki Tsumura & Noriko Nemoto & Katsumasa Kawahara & Minoru Kato & Jun Kotera & Kazuaki Nakamura & Akito Tanoue & Junji Yamauchi
Received: 20 March 2013 / Accepted: 19 April 2013 # Springer Science+Business Media New York 2013
Abstract The myelin sheath consists of a unique multiple layer structure that acts as an insulator between neuronal axons to enhance the propagation of the action potential. In neuropathies such as demyelinating or dismyelinating diseases, chronic demyelination and defective remyelination occur repeatedly, leading to more severe neuropathy. As yet, little is known about the possibility of drug targetspecific medicine for such diseases. In the developing Tomohiro Torii and Yuki Miyamoto contributed equally to this work. T. Torii : Y. Miyamoto : K. Nakamura : A. Tanoue : J. Yamauchi Molecular Pharmacology Group, Department of Pharmacology, National Research Institute for Child Health and Development 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan N. Onami : H. Tsumura Laboratory Animal Resource Facility, National Research Institute for Child Health and Development Setagaya, Tokyo 157-8535, Japan N. Nemoto Bioimaging Research Center, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan K. Kawahara : J. Yamauchi Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan M. Kato : J. Kotera Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba, Yokohama 227-0033, Japan J. Yamauchi (*) The Japan Human Health Sciences Foundation, Chuo, Tokyo 103-0001, Japan e-mail: [email protected]
peripheral nervous system (PNS), myelin sheaths form as Schwann cells wrap individual axons. It is thought that the development of a drug promoting myelination by Schwann cells would provide effective therapy against peripheral nerve disorders: to test such treatment, genetically modified mice overexpressing the drug target molecules are needed. We previously identified an Arf6 activator, the guaninenucleotide exchange factor cytohesin-1, as the signaling molecule controlling myelination of peripheral axons by Schwann cells; yet, the important issue of whether cytohesin-1 itself promotes myelin thickness in vivo has remained unclear. Herein, we show that, in mouse PNS nerves, Schwann cellspecific expression of wild-type cytohesin-1 exhibits enhanced myelin thickness. Downstream activation of Arf6 is also seen in these transgenic mice, revealing the involvement of the cytohesin-1 and Arf6 signaling unit in promoting myelination. These results suggest that cytohesin-1 may be a candidate for the basis of a therapy for peripheral neuropathies through its enhancement of myelin thickness. Keywords Cytohesin-1 . Arf6 . Transgenic mouse . Schwann cell . Myelination
Introduction Neuropathies in peripheral nerves are often related to demyelinating diseases. Genetic disorder
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