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The Journal of Neuroscience, February 9, 2005, 25(6):1550-1559; doi:10.1523/JNEUROSCI.3082-04.2005

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Neurobiology of Disease
Transgenic Expression of Human Connexin32 in Myelinating Schwann Cells Prevents Demyelination in Connexin32-Null Mice

Steven S. Scherer,¹ Yi-Tian Xu,¹ Albee Messing,⁴ Klaus Willecke,³ Kenneth H. Fischbeck,^1,5 and Linda Jo Bone Jeng²

¹Department of Neurology and ²Cell and Molecular Biology Graduate Group, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, ³Institut fuer Genetik der Universitat Bonn, Abteilung Molekulargenetik, D-53117 Bonn, Germany, ⁴Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, and ⁵Neurogenetics Branch, National Institute of Neurological Disorders and Stroke-National Institutes of Health, Bethesda, Maryland 20892-1250

Mutations in Gap Junction 1 (GJB1), the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells. Male mice expressing the human transgene were crossed with female Gjb1/cx32-null mice; the resulting male offspring were all cx32-null (on the X chromosome), and one-half were transgene positive. In these transgenic mice, all of the Cx32 was derived from the expression of the transgene and was found in the sciatic nerve but not in the spinal cord or the liver. Furthermore, the Cx32 protein was properly localized (within incisures and paranodes) in myelinating Schwann cells. Finally, the expression of human Cx32 protein "rescued" the phenotype of cx32-null mice, because the transgenic mice have significantly fewer demyelinated or remyelinated axons than their nontransgenic littermates. These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X.

Key words: axon-Schwann cell interactions; Charcot-Marie-Tooth disease; CMT; myelin; Schwann cells; gap junctions; Cx32

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Received July 28, 2004; revised January 3, 2005; accepted January 3, 2005.

This article has been cited by other articles:

				I. Sargiannidou, N. Vavlitou, S. Aristodemou, A. Hadjisavvas, K. Kyriacou, S. S. Scherer, and K. A. Kleopa Connexin32 Mutations Cause Loss of Function in Schwann Cells and Oligodendrocytes Leading to PNS and CNS Myelination Defects J. Neurosci., April 15, 2009; 29(15): 4736 - 4749. [Abstract] [Full Text] [PDF]

				M. E. Shy, C. Siskind, E. R. Swan, K. M. Krajewski, T. Doherty, D. R. Fuerst, P. J. Ainsworth, R. A. Lewis, S. S. Scherer, and A. F. Hahn CMT1X phenotypes represent loss of GJB1 gene function Neurology, March 13, 2007; 68(11): 849 - 855. [Abstract] [Full Text] [PDF]

				Y. Huang, E. E. Sirkowski, J. T. Stickney, and S. S. Scherer Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells J. Neurosci., August 3, 2005; 25(31): 7111 - 7120. [Abstract] [Full Text] [PDF]

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