Modification of Schwann cell phenotype withPlp transgenes: Evidence that the PLP and DM20 isoproteins are targeted to different cellular domains

Proteolipid protein (PLP) and its smaller isoform DM20 constitute the major myelin proteins of the CNS. Mutations of the X‐linked Plp gene cause the heterogeneous syndromes of Pelizaeus‐Merzbacher disease (PMD) and spastic paraplegia (SPG) in man and similar dysmyelinating disorders in a range of animal species. A variety of mutations including missense mutations, deletions, and duplications are responsible. Missense mutations cause a predicted alteration in primary structure of the encoded protein(s) and are generally associated with early onset of signs and generalised dysmyelination. The severity of the phenotype varies according to the particular codon involved and the influence of uncharacterised modifying genes. There is some evidence that the dysmyelination results from the altered protein acquiring a novel function deleterious to the oligodendrocyte's function. Transgenic mice carrying extra copies of the Plp gene provide a valid model of PMD/SPG due to gene duplication. Depending on the gene dosage, the phenotype can vary from early onset of severe and lethal dysmyelination through to a very late onset of a tract‐specific demyelination and axonal degeneration. Mice with a null mutation of the Plp gene assemble and maintain normal amounts of myelin but develop a progressive axonopathy, again demonstrating tract specificity. The results indicate that the functions of PLP are far from clear. There is good evidence that it is involved in the formation of the intraperiod line of myelin, and the results from the knockout and transgenic mice suggest a role in the interaction of oligodendrocyte and axon. Microsc. Res. Tech. 41:344–358, 1998. © 1998 Wiley‐Liss, Inc.

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Expression of a dominant negative IFN‐γreceptor on mouse oligodendrocytes

González

Bergmann

Fuss

et al. 2005

Glia

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The interferon-gamma (IFN-gamma) receptor is expressed by all nucleated cells, and binding of its cognate ligand, IFN-gamma, induces a wide variety of biological functions. Transgenic mice expressing a dominant negative IFN-gamma receptor 1 (IFN-gammaR1DeltaIC) on oligodendrocytes under control of the myelin proteolipid protein promoter are described. The mRNA encoding the transgene was only detected in the nervous system and protein expression was confirmed by immunohistochemistry. Transgenic receptor expression does not alter myelination and the mice exhibited no clinically apparent phenotype. Consistent with the restricted nervous system expression of the transgene, no alterations in peripheral immune responses were detected. Flow cytometric analysis demonstrated constitutive expression of both the IFN-gammaR1DeltaIC transgene and the endogenous IFN-gamma receptor 2 at high levels on oligodendrocytes derived from the transgenic mice. These oligodendrocytes also exhibited decreased STAT1 phosphorylation in response to IFN-gamma, confirming dominant negative transgene function. Transgenic mice in which oligodendrocytes have a diminished ability to respond to IFN-gamma showed delayed virus clearance from oligodendroglia compared with wild-type mice. This model will allow evaluation of oligodendrocyte responses to this critical cytokine during CNS inflammation.

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Modification of Schwann cell phenotype withPlp transgenes: Evidence that the PLP and DM20 isoproteins are targeted to different cellular domains

Cited by 26 publications

References 41 publications

Aberrant dendrite growth in central nervous system white matter induced by a mutant proteolipid protein transgene

Aberrant dendrite growth in central nervous system white matter induced by a mutant proteolipid protein transgene

Current concepts of PLP and its role in the nervous system

Expression of a dominant negative IFN‐γreceptor on mouse oligodendrocytes

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