FAILURE OF CENTRAL-NERVOUS-SYSTEM MYELINATION IN MBP C-MYC TRANSGENICMICE - EVIDENCE FOR C-MYC CYTOTOXICITY/

c-myc is a member of the helix-loop-helix/leucine zipper family of pro teins that modulate the transcriptional activity of specific target ge nes, Although aberrant c-myc expression has been reported to play a ro le in multistage carcinogenesis in astrocytic gliomas, little is known about the effects of the expression of c-myc on oligodendrocytes. Usi ng transgenic animals expressing a human C-myc oncogene under transcri ptional control of the myelin basic protein gene, we investigated the effect of overexpression of this oncogene in oligodendrocytes, The MBP /c-myc transgenic mice developed severe neurological disturbances char acterized by action tremors and recurrent seizures? and premature deat h during postnatal weeks three to five. Affected transgenic mice of va rious strains had severely hypomyelinated central nervous systems and expressed low levels of c-myc, myelin basic protein (MBP) and proteoli pid protein (PLP) mRNAs in the brain, These c-myc transgenic mice also exhibited an increased number of TUNEL positive nuclei, which in most cases were located in cells that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in the c- myc transgenic mice, including heterozygous mice from two strains that had normal lifespans, These observations indicate that the myelin def iciency observed in the MBP/c-myc transgenic animals results from a cy totoxic effect of the c-myc transgene.