CMT 1X - Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice

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J Neurosci. 2005 Feb 9;25(6):1550-9.

Transgenic expression of human connexin32 in myelinating Schwann cells

prevents demyelination in connexin32-null mice.

Scherer SS, Xu YT, Messing A, Willecke K, Fischbeck KH, Jeng LJ.

Department of Neurology and Cell and Molecular Biology Graduate Group,

The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

19104-6077, USA.

Mutations in Gap Junction beta1 (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.