title: Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice.
abstract: We report a method for introducing mtDNA mutations into the mouse female germ line by means of embryonic stem (ES) cell cybrids. Mitochondria were recovered from the brain of a NZB mouse by fusion of synaptosomes to a mtDNA-deficient (rho degrees ) cell line. These cybrids were enucleated and the cytoplasts were electrofused to rhodamine-6G (R-6G)-treated female ES cells. The resulting ES cell cybrids permitted transmission of the NZB mtDNAs through the mouse maternal lineage for three generations. Similarly, mtDNAs from a partially respiratory-deficient chloramphenicol-resistant (CAP(R)) cell line also were introduced into female chimeric mice and were transmitted to the progeny. CAP(R) chimeric mice developed a variety of ocular abnormalities, including congenital cataracts, decreased retinal function, and hamaratomas of the optic nerve. The germ-line transmission of the CAP(R) mutation resulted in animals with growth retardation, myopathy, dilated cardiomyopathy, and perinatal or in utero lethality. Skeletal and heart muscle mitochondria of the CAP(R) mice were enlarged and atypical with inclusions. This mouse ES cell-cybrid approach now provides the means to generate a wide variety of mouse models of mitochondrial disease.
authors: Center for Molecular Medicine, Departments of Dermatology and Pathology and Division of Animal Resources, Emory University School of Medicine, 1462 Clifton Road, Atlanta, GA 30322, USA.
authors: J E
authors: JE
authors: Sligh
authors: S E
authors: SE
authors: Levy
authors: K G
authors: KG
authors: Waymire
authors: P
authors: P
authors: Allard
authors: D L
authors: DL
authors: Dillehay
authors: S
authors: S
authors: Nusinowitz
authors: J R
authors: JR
authors: Heckenlively
authors: G R
authors: GR
authors: MacGregor
authors: D C
authors: DC
authors: Wallace
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002460:Cell Line; D002678:Chimera; D002701:Chloramphenicol / Q000494:pharmacology; D004272:DNA, Mitochondrial; D004351:Drug Resistance; D005260:Female; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D010063:Ovum; D010375:Pedigree; D010641:Phenotype; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D013234:Stem Cells
chemical_list: D004272:DNA, Mitochondrial; D002701:Chloramphenicol