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Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves

Significance Statement

Arf6-specific guanine-nucleotide exchange factor cytohesin-2 could be a new molecular target for promoting myelination. Right panel indicates the peripheral nerve cross-section photograph in MPZ-Cre-driven cytohesin-2-floxed mice (reduced myelin thickness) in electron microscopy (2500-fold). Left panel indicates a control sciatic nerve cross section.

Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves. Global Medical Discovery

 

 

 

 

 

 

 

 

Journal Reference

Torii T1, Ohno N2, Miyamoto Y3, Kawahara K3, Saitoh Y4, Nakamura K3, Takashima S5, Sakagami H6, Tanoue A3, Yamauchi J7. Biochem Biophys Res Commun. 2015 Mar 28. pii: S0006-291X(15)00579-3.

Show Affiliations

1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.

2Interdisciplinary 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.

3Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.

4Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.

5Glycobiology Research Unit, The Noguchi Institute, Itabashi, Tokyo 173-0003, Japan.

6Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.

7Department 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: [email protected]

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 myelinationprocess, 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 Arf6activity 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.

Copyright © 2015 Elsevier Inc. All rights reserved.

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