Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage.
Proteolipid protein (PLP) is an integral membrane protein of CNS myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and myelin deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, 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 overexpression results in a novel phenotype characterized by severe hypomyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. Dysmyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.
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Cedars-Sinai Medical Center, Los Angeles, California 90048.
Schneider
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Griffiths
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Nave
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D000818:Animals; D001483:Base Sequence; D004303:Dosage Compensation, Genetic; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology
D015335:Molecular Probes; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein