Insertional mutagenesis inducing hypomyelination in transgenic mice

Abstract

Investigations of myelin disorders, in particular multiple sclerosis (MS), have concentrated on immunemediated damage to formed myelin, while there has been less emphasis on the molecular genetics of myelin formation. We have generated a transgenic mouse mutant (designated 2-50) which carries an insertional mutation in a locus regulating myelination. These mice carry a transgene comprising 1.3 Kb of the mouse myelin basic protein (MBP) promoter conjugated to a fragment containing exons 2 and 3 of the human c-myc gene. Positive mice show a significant reduction in myelin compared to controls and a shivering phenotype. Unlike other myelin mutants, all 2-50 mice lose the shivering phenotype and breed normally. Expression of c-myc is detectable in only 65% of transgene-carrying mice, and when present occurs at extremely low levels. This shows that the phenotype is caused by insertional inactivation of a gene necessary for myelination rather than ectopic expression of the transgene. The transgene was found by in situ hybridization to be inserted into a single site which is very distally located on chromosome 9. The 2-50 mice represent a unique model which will be ideal for investigating the molecular basis of myelin assembly and for developing gene therapy to promote remyelination in conditions such as MS.