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Molecular and Cellular Biology, May 2004, p. 3949-3956, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3949-3956.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Ndrg1-Deficient Mice Exhibit a Progressive Demyelinating Disorder of Peripheral Nerves

Tomohiko Okuda,1 Yujiro Higashi,2 Koichi Kokame,1 Chihiro Tanaka,1 Hisato Kondoh,2 and Toshiyuki Miyata1*

National Cardiovascular Center Research Institute, Suita, Osaka 565-8565,1 Laboratory of Developmental Biology, Graduate School of Frontier Bioscience, Osaka University, Suita, Osaka 565-0871, Japan2

Received 28 August 2003/ Returned for modification 3 November 2003/ Accepted 10 January 2004

NDRG1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Marie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy, leading to severe disability in adulthood. In this study, we generated mice lacking Ndrg1 to analyze its function and elucidate the pathogenesis of Charcot-Marie-Tooth disease type 4D. Histological analysis showed that the sciatic nerve of Ndrg1-deficient mice degenerated with demyelination at about 5 weeks of age. However, myelination of Schwann cells in the sciatic nerve was normal for 2 weeks after birth. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves. These mice will be used for future analyses of the mechanisms of myelin maintenance.

* Corresponding author. Mailing address: National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Phone: 81-6-6833-5012, ext. 2512. Fax: 81-6-6835-1176. E-mail: miyata{at}ri.ncvc.go.jp.

Molecular and Cellular Biology, May 2004, p. 3949-3956, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3949-3956.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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