PREMATURE ARREST OF MYELIN FORMATION IN TRANSGENIC MICE WITH INCREASED PROTEOLIPID PROTEIN GENE DOSAGE

Proteolipid protein (PLP) is an integral membrane protein of CNS myeli n. Mutations of the X chromosome-linked PLP gene cause glial cell deat h and myelin deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complement ation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overexpressi on results in a novel phenotype characterized by severe hypomyelinatio n and astrocytosis, seizures, and premature death. This demonstrates t hat precise control of the PLP gene is a critical determinant of termi nal oligodendrocyte differentiation. Dysmyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chrom osome, can be caused by doubling of the PLP gene dosage.