Oligodendrocyte programmed cell death and central myelination deficiency induced in transgenic mice by synergism between c-Myc and Oct-6.
The basic helix-loop-helix transcription factor c-Myc is a potent trigger of programmed cell death when overexpressed during late oligodendrocyte development in transgenic mice. Here we provide evidence that c-Myc can act synergistically with the Pit, Oct, Unc homeodomain transcription factor Oct-6 to produce myelin disease pathogenesis in transgenic mice. More than 70% of c-myc/Oct-6 bitransgenic mice, obtained from crosses between phenotypically normal heterozygous mice of various My (c-Myc) and Oc (Oct-6) transgenic strains that express c-myc and oct-6 transgenes under transcriptional control of the myelin basic protein gene, developed severe neurological disturbances characterized by action tremors, recurrent seizures, and premature death. Affected bitransgenic mice exhibited multiple hypomyelinated lesions in the white matter that did not stain with myelin-specific antibodies against myelin basic protein, proteolipid protein, CNPase, and myelin-associated glycoprotein. The mice also exhibited a larger number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling positive cells in the white matter as well as ultrastructural evidence of glial cell death and astrogliosis. These observations indicate that the myelin lesions observed in the c-myc/oct-6 bitransgenic mice result from the untimely programmed cell death of oligodendroglia and that the c-myc and oct-6 transgenes act synergistically in producing the lesions.
Jensen
N A
NA
Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark. naj@imbg.ku.dk
West
M J
MJ
Celis
J E
JE
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000172:deficiency*; D050816:Octamer Transcription Factor-6; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D004676:Myelin Basic Protein; C494180:Pou3f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D050816:Octamer Transcription Factor-6