A COMBINATION OF PLP AND DM20 TRANSGENES PROMOTES PARTIAL MYELINATIONIN THE JIMPY MOUSE

Mutations in the myelin proteolipid protein (PLP) gene, such as that f ound in the jimpy mouse, result in an abnormal structure of the myelin , severe dysmyelination, and a reduction in the number of mature oligo dendrocytes. To examine the functions of the two alternatively spliced isoforms of proteolipid protein, transgenic mice were generated that express either PLP or DM20 cDNAs placed under control of the PLP upstr eam regulatory region. The transgenes were bred into jimpy mice, and t he effect of the transgenes on the dysmyelinating phenotype was analyz ed. Neither the PLP transgene nor the DM20 transgene alone had an effe ct on myelination in the jimpy mice. Combining the two transgenes subs tantially increased the number of myelinated axons, suggesting that th e two alternatively spliced products of the PLP locus perform distinct functions in oligodendrocytes. The enhanced myelination was not suffi cient, however, for completely correcting the dysmyelinating phenotype of the jimpy mice, nor was it accompanied by the restoration of norma l levels of myelin gene expression. The inability to rescue the jimpy phenotype is most likely attributable to a dominant negative action of the abnormal proteolipid proteins present in jimpy mice. These result s demonstrate the complexity of proteolipid protein function in myelin ation.