Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice

James E. Sligh, Shawn E. Levy, Katrina G. Waymire, Paulette Allard, Dirck L. Dillehay, Steven Nusinowitz, John R. Heckenlively, Grant R. MacGregor, Douglas C. Wallace

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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 (ρ°) 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 (CAPR) cell line also were introduced into female chimeric mice and were transmitted to the progeny. CAPR 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 CAPR mutation resulted in animals with growth retardation, myopathy, dilated cardiomyopathy, and perinatal or in utero lethality. Skeletal and heart muscle mitochondria of the CAPR 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.

Original languageEnglish (US)
Pages (from-to)14461-14466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number26
DOIs
StatePublished - Dec 19 2000

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    Sligh, J. E., Levy, S. E., Waymire, K. G., Allard, P., Dillehay, D. L., Nusinowitz, S., Heckenlively, J. R., MacGregor, G. R., & Wallace, D. C. (2000). Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proceedings of the National Academy of Sciences of the United States of America, 97(26), 14461-14466. https://doi.org/10.1073/pnas.250491597